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Sample records for chemotherapeutic agents effectively

  1. [Chemotherapeutic agents under study].

    PubMed

    Kawahara, S

    1998-12-01

    The development of new drugs with strong antituberculous activity and fewer side effects which are not cross-resistant to conventional antituberculosis drugs is urgently desired now. The chemotherapeutic agents under study which are considered a candidate for a new antituberculosis drug are listed below. 1) Rifamycin derivatives: rifabutin, rifapentin, KRM-1648, FCE-22250, 22807, CGP-7040, 27557, 29035, 29861, P-DEA, SPA-S-565, R-76-1. 2) New quinolones: ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, CS-940, Du-6859a. 3) Phenazines: clofazimine, B746, B4101, B4154, B4157. 4) Pyrazinamide derivatives: N-hydroxy pyrazinamide, N-hydroxy pyrazinamide-4-oxide. 5) Nitroimidazole derivatives: metronidazole et al.

  2. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

    PubMed

    Bao, Jiaolin; Huang, Borong; Zou, Lidi; Chen, Shenghui; Zhang, Chao; Zhang, Yulin; Chen, Meiwan; Wan, Jian-Bo; Su, Huanxing; Wang, Yitao; He, Chengwei

    2015-01-01

    Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

  3. Effects of St. John’s Wort and Vitamin E on Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2002-05-01

    Johns wort may decrease peak levels of doxorubicin. Further studies will help to determine whether important interactions occur between these nutrients and cancer chemotherapeutic agents....doxorubicin. Our studies suggest that even relatively high doses of vitamin E do not adversely affect the toxicity of doxorubicin. On the other hand, St

  4. Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review

    PubMed Central

    Eitsuka, Takahiro; Tatewaki, Naoto; Nishida, Hiroshi; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2016-01-01

    Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy. PMID:27669218

  5. Identification of plumbagin and sanguinarine as effective chemotherapeutic agents for treatment of schistosomiasis☆

    PubMed Central

    Zhang, Si-Ming; Coultas, Kristen A.

    2012-01-01

    Schistosomiasis, a snail-borne parasitic disease, affects more than 200 million people worldwide. Currently the treatment of schistosomiasis relies on a single therapy of praziquantel, a drug developed over 30 years ago. Thus, there is an urgent need to develop alternative antischistosomal drugs. In the pursuit of novel antischistosomal drugs, we examined the antischistosomal activities of 45 compounds that had been reported to exhibit antimicrobial and/or antiparasitic activities. Two plant-derived compounds, plumbagin and sanguinarine, were found to possess potent antischistosomal activities in vitro. For both the compounds, a concentration of 10 μM (equivalent to 1.88 μg/ml for plumbagin and 3.68 μg/ml for sanguinarine) resulted in 100% mortality at 48 h, which meets the World Health Organization’s (WHO) criterion of “hit” compounds for the control of schistosomiasis. Morphological changes and tegumental alterations of the dead worms treated by the two compounds were quite different. The significant morphological changes of worms after treatment by the two compounds suggest the two compounds target different biological pathways, both of which result in parasite’s death. This study provides evidence to suggest plumbagin and sanguinarine have real potential as effective alternative chemotherapeutic agents for the treatment of schistosomiasis. PMID:23641325

  6. PHB-Based Gels as Delivery Agents of Chemotherapeutics for the Effective Shrinkage of Tumors.

    PubMed

    Wu, Yun-Long; Wang, Han; Qiu, Ying-Kun; Liow, Sing Shy; Li, Zibiao; Loh, Xian Jun

    2016-10-01

    Injectable thermogel to deliver chemotherapeutics in a minimally invasive manner and to achieve their long term sustained release at tumor sites to minimize side effects is attractive for chemotherapy and precision medicine, but its rational design remains a challenge. In this work, a copolymer with natural biodegradable poly[(R)-3-hydroxybutyrate] (PHB), hydrophilic poly(ethylene glycol), and temperature sensitive poly(propylene glycol) blocks linked by urethane linkages is designed to show thermogelling characteristics which are beneficial for minimally invasive injection and safe degradation. This thermogelling polymer possesses in vitro biocompatibility with very low cyto-toxicity in HEK293 cells. Furthermore, it is able to form the gel to achieve the controllable release of paclitaxel (PTX) and doxorubicin (DOX) by adjusting polymer concentrations. A rodent model of hepatocarcinoma has been performed to demonstrate the in vivo applications of this PHB-based thermogel. The drug-loaded thermogel has been intratumorally injected and both PTX-loaded and DOX-loaded thermogel have significantly slowed down tumor growth. This work represents the first time that injectable PHB thermogels have possessed good controllable release effect of chemotherapeutics against the in vivo model of tumors and will benefit various applications, including on-demand drug delivery and personalized medicine.

  7. Nanospheric Chemotherapeutic and Chemoprotective Agents

    DTIC Science & Technology

    2008-09-01

    targeting the drug-nanosphere complex to diseased cells, thereby minimizing unwanted effects on healthy cells. This report describes the optimization of...military and civilian requirements for effective breast cancer chemotherapy : nontoxic administration, increased bioavailability, prolonged circulation...provide highly effective delivery of hydrophobic paclitaxel to human tumor cells in vitro; (b) tyrosine-derived nanospheres exhibit no toxicity as

  8. Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma

    PubMed Central

    Heinen, Tiago Elias; dos Santos, Rafael Pereira; da Rocha, Amanda; dos Santos, Michel Pinheiro; da Costa Lopez, Patrícia Luciana; Filho, Marco Aurélio Silva; Souza, Bárbara Kunzler; da Rosa Rivero, Luís Fernando; Becker, Ricardo Gehrke; Gregianin, Lauro José; Brunetto, Algemir Lunardi; Brunetto, André Tesainer; de Farias, Caroline Brunetto; Roesler, Rafael

    2016-01-01

    Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of β-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES. PMID:27145455

  9. STAT3 Inhibition by Microtubule-Targeted Drugs: Dual Molecular Effects of Chemotherapeutic Agents

    PubMed Central

    Walker, Sarah R.; Chaudhury, Mousumi; Frank, David A.

    2011-01-01

    To improve the effectiveness of anti-cancer therapies, it is necessary to identify molecular targets that are essential to a tumor cell but dispensable in a normal cell. Increasing evidence indicates that the transcription factor STAT3, which regulates the expression of genes controlling proliferation, survival, and self-renewal, constitutes such a target. Recently it has been found that STAT3 can associate with the cytoskeleton. Since many of the tumors in which STAT3 is activated, such as breast cancer and ovarian cancer, are responsive to drugs that target microtubules, we examined the effect of these compounds on STAT3. We found that microtubule stabilizers, such as paclitaxel, or microtubule inhibitors, such as vinorelbine, decrease the activating tyrosine phosphorylation of STAT3 in tumor cells and inhibit the expression of STAT3 target genes. Paclitaxel decreases the association between STAT3 and microtubules, and appears to decrease STAT3 phosphorylation through induction of a negative feedback regulator. The cytotoxic activity of paclitaxel in breast cancer cell lines correlates with its ability to decrease STAT3 phosphorylation. However, consistent with the necessity for expression of a negative regulator, treatment of resistant MDA-MB-231 cells with the DNA demethylating agent 5-azacytidine restores the ability of paclitaxel to block STAT3-dependent gene expression. Finally, the combination of paclitaxel and agents that directly target STAT3 has beneficial effects in killing STAT3-dependent cell lines. Thus, microtubule-targeted agents may exert some of their effects by inhibiting STAT3, and understanding this interaction may be important for optimizing rational targeted cancer therapies. PMID:21949561

  10. Targeted Delivery of Chemotherapeutic Agents Using Improved Radiosensitive Liquid Core Microcapsules and Assessment of Their Antitumor Effect

    SciTech Connect

    Harada, Satoshi Ehara, Shigeru; Ishii, Keizo; Yamazaki, Hiromichi; Matsuyama, Shigeo; Sato, Takahiro; Oikawa, Shyoichi; Kamiya, Tomihiro; Arakawa, Kazuo; Yokota, Wataru; Sera, Koichiro; Ito, Jyun

    2009-10-01

    Purpose: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. Methods and Materials: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 {mu}g) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl{sub 2} solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy {sup 60}Co {gamma}-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. Results: Microcapsules that had been polymerized using a 4.34% CaCl{sub 2} solution supplemented with 5.0 x 10{sup -3}% (10{sup -3}% meant or 10%{sup -3}) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. Conclusion: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

  11. Effects of Saint John’s Wort and Vitamin E on Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2005-05-01

    standard diet and those supplemented with vitamin E (Table 1). None of the treatment means were significantly different from the control means. Table 1...different from the standard diet group (Figure 3). There was no effect of vitamin E supplementation on Hct or Hctfall after docetaxel treatment (data not...E [ High E 5000- •4000- •SEM 8 3000-2000- -1i 1000- 12 15 18 20 Docetaxel Dose (mg/kg) Figure 2. Nadir WBC counts measured 4 days after treatment of

  12. Warming Effect on Miriplatin-Lipiodol Suspension as a Chemotherapeutic Agent for Transarterial Chemoembolization for Hepatocellular Carcinoma: Preliminary Clinical Experience

    SciTech Connect

    Kora, Shinn-ichi; Urakawa, Hiroshi; Mitsufuji, Toshimichi; Osame, Akinobu; Higashihara, Hideyuki; Yoshimitsu, Kengo

    2013-08-01

    PurposeTo retrospectively elucidate the preliminary clinical impact of warmed miriplatin-lipiodol suspension (MPT-LPD) when used as a chemotherapeutic agent for transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).Materials and MethodsBetween June and December 2010, TACE was performed with MPT-LPD at room temperature (RT group), and after January 2011, TACE with MPT-LPD warmed to 40 Degree-Sign C was performed (W group). The intraarterial appearance of MPT-LPD immediately after injection through microcatheters at the second-order branches was compared between the two groups with a 5-point grading system. Local therapeutic effects of HCCs as assessed by follow-up computed tomography (CT) obtained 1-3 months after TACE were compared between the groups with a 4-point grading system (TE1-TE4). After April 2011, angiography-assisted CT was routinely performed at TACE, and HCCs that revealed apparent corona enhancement (CE) were retrospectively selected. The degree of concordance between CE and MPT-LPD accumulation as assessed by CT immediately after TACE was assessed with a 3-point grading scale.ResultsMPT-LPD therapy resulted in a smooth and continuous appearance in the W group (grades 1, 2, 3, 4, and 5 were, respectively, 1, 2, 11, 18, and 4) compared to the RT group (4, 0, 1, 2, and 0). The W group (TE1, TE2, TE3, and TE4 were 1, 9, 11, and 12) revealed better local therapeutic effects than the RT group (6, 3, 9, and 0) (p < 0.05). CE was found in 26 HCC nodules, and concordance between CE and MPT-LPD accumulation was observed in 66 % (grades 1, 2, and 3 were, respectively, 2, 8, and 19).ConclusionWarmed MPT-LPD flowed more smoothly within vascular lumen, passed through tumor sinusoid of HCC, and had better local therapeutic effects at short-term observation than MPT-LPD at room temperature.

  13. Endoscopic spectral domain optical coherence tomography of murine colonic morphology to determine effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer

    NASA Astrophysics Data System (ADS)

    LeGendre-McGhee, Susan; Rice, Photini F. S.; Wall, R. Andrew; Klein, Justin; Luttman, Amber; Sprute, Kyle; Gerner, Eugene; Barton, Jennifer K.

    2012-02-01

    Optical coherence tomography (OCT) is a minimally-invasive imaging modality capable of tracking the development of individual colonic adenomas. As such, OCT can be used to evaluate the mechanisms and effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer models. The data presented here represent part of a larger study evaluating α-difluoromethylornithine (DFMO) and Sulindac as chemopreventive and chemotherapeutic agents using mice treated with the carcinogen azoxymethane (AOM). 27 A/J mice were included in the chemoprevention study, subdivided into four treatment groups (No Drug, DFMO, Sulindac, DFMO/Sulindac). 30 mm lateral images of each colon at eight different rotations were obtained at five different time points using a 2 mm diameter spectral domain OCT endoscopy system centered at 890 nm with 3.5 μm axial resolution in air and 5 μm lateral resolution. Images were visually analyzed to determine number and size of adenomas. Gross photos of the excised colons and histology provided gold standard confirmation of the final imaging time point. Preliminary results show that 100% of mice in the No Drug group developed adenomas over the course of the chemoprevention study. Incidence was reduced to 71.43% in mice given DFMO, 85.71% for Sulindac and 0% for DFMO/Sulindac. Discrete adenoma size did not vary significantly between experimental groups. Additional experiments are currently under way to verify these results and evaluate DFMO and Sulindac for chemotherapeutic applications.

  14. Assessment of the inhibitory effects of different radiation qualities or chemotherapeutic agents on a human melanoma cell line.

    PubMed

    Ristić-Fira, Aleksandra M; Petrović, Ivan M; Korićanac, Lela B; Valastro, Lucia M; Privitera, Giuseppe; Cuttone, Giacomo

    2008-12-01

    The correlation between time dependent viabilities, after applying two radiation qualities and two alkylating agents on HTB140 melanoma cells, has been studied. Irradiations were performed with gamma-rays and 62 MeV protons, close to the Bragg peak maximum, delivering doses of 8-24 Gy. Treatments with fotemustine (FM) and dacarbazine (DTIC) were carried out with concentrations of 0.05-2mM. High radio-resistance of HTB140 cells revealed by a clonogenic assay was confirmed by microtetrasolium and sulforhodamine B, through the surviving fraction at 2 Gy (SF2), being 0.961-0.956 for gamma-rays and 0.931-0.887 for protons. A better efficiency of protons was illustrated by relative biological effectiveness at 2 Gy (RBE), ranging from 1.69 to 1.89. A kinetic study of concentration dependent cytotoxicity indicated that the best effect of the drugs, estimated as the concentration that produces 50% of growth inhibition (IC(50)), was obtained at 48 h, having values of 76 microM for DTIC and 145 microM for FM. The cytostatic ability of the drugs pointed out that the presence of DTIC at 24h, compared to FM, was insufficient to produce an effect. Protons and FM demonstrated their pro apoptotic capacity. Cross-resistance between treatments applied to the HTB140 cells was observed, protons being the most efficient, while DTIC, FM and gamma-rays demonstrated a lower level of cell inactivation.

  15. Current Research and Development of Chemotherapeutic Agents for Melanoma

    PubMed Central

    Hsan, Kyaw Minn; Chen, Chun-Chieh; Shyur, Lie-Fen

    2010-01-01

    Cutaneous malignant melanoma is the most lethal form of skin cancer and an increasingly common disease worldwide. It remains one of the most treatment-refractory malignancies. The current treatment options for patients with metastatic melanoma are limited and in most cases non-curative. This review focuses on conventional chemotherapeutic drugs for melanoma treatment, by a single or combinational agent approach, but also summarizes some potential novel phytoagents discovered from dietary vegetables or traditional herbal medicines as alternative options or future medicine for melanoma prevention. We explore the mode of actions of these natural phytoagents against metastatic melanoma. PMID:24281076

  16. Augmentation of Chemotherapeutic Infusion Effect by TSU-68, an Oral Targeted Antiangiogenic Agent, in a Rabbit VX2 Liver Tumor Model

    SciTech Connect

    Kim, Hyo-Cheol; Chung, Jin Wook Choi, Seung Hong; Im, Seock-Ah; Yamasaki, Yasundo; Jun, Suryoung; Jae, Hwan Jun; Park, Jae Hyung

    2012-02-15

    Purpose: This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model. Methods: This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performed before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections. Results: According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02). Conclusions: Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.

  17. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent, 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n=8-10): Saline+Water; 5-FU+Skim Milk; 5-FU+Live TH-4; 5-FU+Supernatant TH-4; and 5-FU+Dead TH-4. 5-FU (150mg.kg(-1)) was administered by a single intraperitoneal injection on day 0; animals were killed on day 4. Treatments were administered daily from days -2 to 3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villous height and area; crypt depth and area, mitotic count and crypt fission; biochemical determination of sucrase and myeloperoxidase (MPO) activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalised mitotic counts compared with 5-FU+Skim milk controls. Live and supernatant TH-4 reduced crypt fission by 69% and 48% (p< 0.05), respectively, compared to 5-FU+Skim Milk controls. No significant differences (p> 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalised mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterised by increased crypt fission, such as colorectal carcinoma.

  18. Effects of Streptococcus thermophilus TH-4 on intestinal mucositis induced by the chemotherapeutic agent 5-Fluorouracil (5-FU).

    PubMed

    Whitford, Eleanor J; Cummins, Adrian G; Butler, Ross N; Prisciandaro, Luca D; Fauser, Jane K; Yazbeck, Roger; Lawrence, Andrew; Cheah, Ker Y; Wright, Tessa H; Lymn, Kerry A; Howarth, Gordon S

    2009-03-15

    Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n = 8–10): Saline + Water; 5-FU + Skim Milk; 5-FU+ Live TH-4; 5-FU + Supernatant TH-4; and 5-FU + Dead TH-4.5-FU (150 mg.kg-1) was administered by a single intraperitoneal injection on day zero; animals were killed on day four. Treatments were administered daily from days -2 to +3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villus height and area; crypt depth and area, mitotic count and crypt fission;biochemical determination of sucrase and myeloperoxidase (MPO)activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalized mitotic counts compared with 5-FU + Skim Milk controls. Live and Supernatant TH-4 reduced crypt fission by 69% and 48% (p < 0.05), respectively, compared to 5-FU + Skim Milk controls. No significant differences (p > 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalized mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 Supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterized by increased crypt fission,such as colorectal carcinoma.

  19. In vitro sensitivity of human ovarian tumours to chemotherapeutic agents.

    PubMed Central

    Wilson, A. P.; Neal, F. E.

    1981-01-01

    The in vitro chemosensitivity of primary monolayer cultures of human ovarian tumours to a wide range of chemotherapeutic agents has been determined using 3H-leucine incorporation as an index of cytotoxicity. Of 67 specimens received, 35 have been successfully cultured and tested for chemosensitivity. Drugs tested included alkylating agents, antibiotics, antimitotics, antimetabolites and progestogens. The overall incidence of efficacy of the drugs corresponded with the incidence which might be expected from data on the clinical response rates produced by the various drugs. Cultures from the tumour cells of treated patients generally showed greater resistance than tumours of untreated patients. Correlation between in vitro results and in vivo response was positive in all 8 patients receiving first-line chemotherapy and in 57% (4/7) patients receiving second-line chemotherapy. PMID:6791675

  20. Cinnamaldehyde/chemotherapeutic agents interaction and drug-metabolizing genes in colorectal cancer.

    PubMed

    Yu, Chen; Liu, Shen-Lin; Qi, Ming-Hao; Zou, Xi

    2014-02-01

    Cinnamaldehyde is an active monomer isolated from the stem bark of Cinnamomum cassia, a traditional oriental medicinal herb, which is known to possess marked antitumor effects in vitro and in vivo. The aim of the present study was to examine the potential advantages of using cinnamaldehyde in combination with chemotherapeutic agents commonly used in colorectal carcinoma (CRC) therapy, as well as to investigate the effect of cinnamaldehyde on chemotherapeutic-associated gene expression. The synergistic interaction of cinnamaldehyde and chemotherapeutic agents on human CRC HT-29 and LoVo cells was evaluated using the combination index (CI) method. The double staining with Annexin V conjugated to fluorescein-isothiocyanate and phosphatidylserine was employed for apoptosis detection. The expression of drug-metabolizing genes, including excision repair cross‑complementing 1 (ERCC1), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), breast cancer susceptibility gene 1 (BRCA1) and topoisomerase 1 (TOPO1), all in HT-29 and LoVo cells, with or without the addition of cinnamaldehyde, was examined by quantitative polymerase chain reaction (PCR). Cinnamaldehyde had a synergistic effect on the chemotherapeutic agents cytotoxicity in HT-29 and LoVo cells. In addition, cinnamaldehyde suppressed BRCA1, TOPO1, ERCC1 and TS mRNA expression, except for OPRT expression, which was markedly upregulated. Our findings indicate that cinnamaldehyde appears to be a promising candidate as an adjuvant in combination therapy with 5-fluorouracil (5-FU) and oxaliplatin (OXA), two chemotherapeutic agents used in CRC treatment. The possible mechanisms of its action may involve the regulation of drug‑metabolizing genes.

  1. Graphene Oxide Induced Perturbation to Plasma Membrane and Cytoskeletal Meshwork Sensitize Cancer Cells to Chemotherapeutic Agents.

    PubMed

    Zhu, Jianqiang; Xu, Ming; Gao, Ming; Zhang, Zhihong; Xu, Yong; Xia, Tian; Liu, Sijin

    2017-03-28

    The outstanding physicochemical properties endow graphene materials (e.g., graphene oxide, GO) with beneficial potentials in diverse biomedical fields such as bioimaging, drug delivery, and biomolecular detection. GO recently emerged as a chemosensitizer; however, the detailed molecular basis underlying GO-conducted sensitization and corresponding biological effects are still elusive. Based on our recent findings that GO treatment at sublethal concentrations could impair the general cellular priming state, including disorders of plasma membrane and cytoskeleton construction, we aimed here to explore the mechanism of GO as a sensitizer to make cancer cells more susceptible to chemotherapeutic agents. We discovered that GO could not only compromise plasma membrane and cytoskeleton in J774A.1 macrophages and A549 lung cancer cells at sublethal concentrations without incurring significant cell death but also dampen a number of biological processes. Using the toxicogenomics approaches, we laid out the gene expression signature affected by GO and further defined those genes involved in membrane and cytoskeletal impairments responding to GO. The mechanistic investigation uncovered that the interactions of GO-integrin occurred on the plasma membrane and consequently activated the integrin-FAK-Rho-ROCK pathway and suppressed the expression of integrin, resulting in compromised cell membrane and cytoskeleton and a subsequent cellular priming state. By making use of this mechanism, the efficacy of chemotherapeutic agents (e.g., doxorubicin and cisplatin) could be enhanced by GO pretreatment in killing cancer cells. This study unveiled a feature of GO in cancer therapeutics: sensitizing cancer cells to chemotherapeutic agents by undermining the resistance capability of tumor cells against chemotherapeutic agents, at least partially, by compromising plasma membrane and cytoskeleton meshwork.

  2. Noscapine and its Analogs as Chemotherapeutic Agent: Current updates.

    PubMed

    Tomar, Vartika; Kukreti, Shrikant; Prakash, Satya; Madan, Jitender; Chandra, Ramesh

    2017-01-01

    Recently, noscapine was reported as anticancer drug. Unlike, colchicine and podophyllotoxin, noscapine did not depolymerize microtubules even at stoichiometric concentrations but rather only mitigated their dynamics. Other microtubule-interacting chemotherapeutics, although quite effective, have therapy-limiting toxicities including immunosuppression and peripheral neuropathies. Recurrent cancers often become resistant. Noscapine however remains effective in some such instances, e.g., taxane-resistant ovarian cancer. Noscapine and analogs also do not show signs of neurotoxicity or immunosuppression. In addition, 9-bromo noscapine, Red-9-Br-Nos and other analogs were characterized for their structure and further studied in detail. On the other hand, noscapine was shown to be neuroprotective in mouse model of neurodegenerative disease and in stroke patients. Like low doses of colchicine, noscapine and its analog 9-Br-Noscapine also show anti-inflammatory activities. There are indications of a preventive use of noscapine in ischemiareperfusion injury and fibrosis. The entire biosynthetic pathway of noscapine is encoded as gene cluster within 401 kilo bases of genomic DNA, opening up opportunities for the large-scale biotechnological production of noscapine for medicinal needs. Thus, noscapine and its derivatives (noscapinoids) might be cost-effective and safe components for cancer chemotherapy. Owing to its low toxicity, it also might be useful for preventive use in high-risk situations. This brief review is an update of current research activity and patents on noscapine and its analogs.

  3. 2,3-DIPHENYL-1,4-NAPHTHOQUINONE: A POTENTIAL CHEMOTHERAPEUTIC AGENT AGAINST TRYPANOSOMA CRUZI

    PubMed Central

    Ramos, Enrique I.; Garza, Kristine M.; Krauth-Siegel, R. L.; Bader, Julia; Martinez, Luiz E.; Maldonado, Rosa A.

    2010-01-01

    Chagas disease, caused by Trypanosoma cruzi, is a wide spread infection in Latin America. Currently, only 2 partially effective and highly toxic drugs, i.e., benznidazole and nifurtimox, are available for the treatment of this disease and several efforts are underway in the search for better chemotherapeutic agents. Here, we have determined the trypanocidal activity of 2,3-diphenyl-1,4-naphthoquinone (DPNQ), a novel quinone derivative. In vitro, DPNQ was highly cytotoxic at a low, micromolar concentration (LD50 = 2.5 μM) against epimastigote, cell-derived trypomastigote, and intracellular amastigote forms of T. cruzi, but not against mammalian cells (LD50 = 130 μM). In vivo studies on the murine model of Chagas disease revealed that DPNQ-treated animals (3 doses of 10 mg/kg/day) showed a significant delay in parasitemia peak and higher (up to 60%) survival rate 70 days post-infection, when compared to control group (infected, untreated). We also observed a 2-fold decrease in the parasitemia between the control group (infected, untreated) and the treated group (infected, treated). No apparent drug toxicity effects were noticed in the control group (uninfected, treated). In addition, we determined that DPNQ is the first competitive inhibitor of T. cruzi lipoamide dehydrogenase (TcLipDH) thus far described. Our results indicate that DPNQ is a promising chemotherapeutic agent against T. cruzi. PMID:18788881

  4. The chemotherapeutic agent paclitaxel selectively impairs learning while sparing source memory and spatial memory.

    PubMed

    Smith, Alexandra E; Slivicki, Richard A; Hohmann, Andrea G; Crystal, Jonathon D

    2017-03-01

    Chemotherapeutic agents are widely used to treat patients with systemic cancer. The efficacy of these therapies is undermined by their adverse side-effect profiles such as cognitive deficits that have a negative impact on the quality of life of cancer survivors. Cognitive side effects occur across a variety of domains, including memory, executive function, and processing speed. Such impairments are exacerbated under cognitive challenges and a subgroup of patients experience long-term impairments. Episodic memory in rats can be examined using a source memory task. In the current study, rats received paclitaxel, a taxane-derived chemotherapeutic agent, and learning and memory functioning was examined using the source memory task. Treatment with paclitaxel did not impair spatial and episodic memory, and paclitaxel treated rats were not more susceptible to cognitive challenges. Under conditions in which memory was not impaired, paclitaxel treatment impaired learning of new rules, documenting a decreased sensitivity to changes in experimental contingencies. These findings provide new information on the nature of cancer chemotherapy-induced cognitive impairments, particularly regarding the incongruent vulnerability of episodic memory and new learning following treatment with paclitaxel.

  5. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents.

    PubMed

    Yu, Yan; Xie, Yangchun; Cao, Lizhi; Yang, Liangchun; Yang, Minghua; Lotze, Michael T; Zeh, Herbert J; Kang, Rui; Tang, Daolin

    2015-01-01

    Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Development of resistance to chemotherapeutic agents is a major hurdle in the effective treatment of patients with AML. The quinazolinone derivative erastin was originally identified in a screen for small molecules that exhibit synthetic lethality with expression of the RAS oncogene. This lethality was subsequently shown to occur by induction of a novel form of cell death termed ferroptosis. In this study we demonstrate that erastin enhances the sensitivity of AML cells to chemotherapeutic agents in an RAS-independent manner. Erastin dose-dependently induced mixed types of cell death associated with ferroptosis, apoptosis, necroptosis, and autophagy in HL-60 cells (AML, NRAS_Q61L), but not Jurkat (acute T-cell leukemia, RAS wild type), THP-1 (AML, NRAS_G12D), K562 (chronic myelogenous leukemia, RAS wild type), or NB-4 (acute promyelocytic leukemia M3, KRAS_A18D) cells. Treatment with ferrostatin-1 (a potent ferroptosis inhibitor) or necrostatin-1 (a potent necroptosis inhibitor), but not with Z-VAD-FMK (a general caspase inhibitor) or chloroquine (a potent autophagy inhibitor), prevented erastin-induced growth inhibition in HL-60 cells. Moreover, inhibition of c-JUN N-terminal kinase and p38, but not of extracellular signal-regulated kinase activation, induced resistance to erastin in HL-60 cells. Importantly, low-dose erastin significantly enhanced the anticancer activity of 2 first-line chemotherapeutic drugs (cytarabine/ara-C and doxorubicin/adriamycin) in HL-60 cells. Collectively, the induction of ferroptosis and necroptosis contributed to erastin-induced growth inhibition and overcame drug resistance in AML cells.

  6. Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

    PubMed Central

    Kang, Lin; Gao, Zhonggao; Huang, Wei; Jin, Mingji; Wang, Qiming

    2015-01-01

    The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID:26579443

  7. Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells

    PubMed Central

    Ma, Wenzhe; Feng, Senling; Yao, Xiaojun; Yuan, Zhongwen; Liu, Liang; Xie, Ying

    2015-01-01

    Multidrug resistance (MDR) is the major obstacle to the successful chemotherapy treatment of many cancers. Here we found that nobiletin, a citrus methoxyflavone, significantly sensitized ABCB1 overexpressing cells A2780/T and A549/T to chemotherapeutic agents such as paclitaxel (a 433-fold reversal of MDR to PTX at 9 μM), doxorubicin (DOX), docetaxel and dounorubicin. Nobiletin profoundly inhibited ABCB1 transporter activity since it significantly increased the intracellular accumulation of DOX and Flutax-2 in A2780/T cells and decreased the efflux of ABCB1 substrates in Caco2 cells without altering the mRNA and protein expression of ABCB1. Moreover, nobiletin stimulated ATPase activity and inhibited verapamil-stimulated ATPase activity in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, molecular docking analysis also identified favorable binding of nobiletin with the transmemberane region site 1 of homology modeled human ABCB1 transporter. Moreover, the Nrf2 protein expression and phosphorylation levels of AKT/ERK were suppressed by co-treated with nobiletin and PTX at the reversal concentrations, suggesting that inhibition of the AKT/ERK/Nrf2 pathway was associated with the sensitizing effect of nobiletin. These findings encourage further animal and clinical MDR studies with the combination therapy of nobiletin and chemotherapeutic drugs. PMID:26689156

  8. Inhibition of HIV replication in vitro by clinical immunosuppressants and chemotherapeutic agents

    PubMed Central

    2013-01-01

    Background Recent studies have suggested that a functional cure for HIV-1 infection, purportedly resultant from allogeneic bone marrow transplantation, may be possible. Additionally, the first such patient was treated with whole-body irradiation, immunosuppressants, and the chemotherapeutic, cytarabine. However, the precise role of the coinciding medical interventions in diminishing detectable HIV reservoirs remains unstudied. Findings In this article, we demonstrate that the immunosuppressants, mycophenolic acid and cyclosporine, and the chemotherapeutic, cytarabine, are potent antiretroviral agents at clinically relevant dosages. These drugs strongly inhibit HIV-1 replication in a GFP indicator T cell line and peripheral blood mononuclear cells (PBMC). Conclusions Our study suggests that certain clinical immunosuppressants and chemotherapeutic agents may act combinatorially to inhibit HIV infection. Additionally, chemotherapy-mediated cytotoxicity may also affect the stability of viral reservoirs. Thus, further study is needed to examine potential therapeutic value of these interventions in patients. PMID:23672887

  9. [The sensitivity of anaerobic bacteria to chemotherapeutic agents (Zurich, 1991)].

    PubMed

    Wüst, J; Hardegger, U

    1991-12-27

    There have been numerous reports on resistance of anaerobic bacteria against antimicrobial agents. Therefore, to assess the situation in Zurich, 187 anaerobic strains of various bacterial genera, isolated from clinical specimens during winter 1990/91, were tested for their susceptibility to antimicrobial agents active against anaerobic bacteria. Besides the Bacteroides fragilis group, which is naturally resistant against penicillin, 30% of isolates of other Bacteroides species were also resistant against penicillin. In general, anaerobes have remained susceptible to cefoxitin, chloramphenicol, clindamycin, imipenem, the 5-nitroimidazoles (metronidazole, ornidazole) as well as combinations of beta-lactam antibiotics with beta-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam). Because rare strains resistant against cefoxitin, clindamycin and beta-lactams plus beta-lactamase inhibitors can be found, at least isolates from specific clinical situations should be tested for antimicrobial susceptibility. These are strains isolated from patients with brain abscess, endocarditis, osteomyelitis, arthritis, infected implants and prosthesis as well as those from persisting or recurrent bacteremia. Because the agar diffusion test yields unreliable results, minimal inhibitory concentration should be determined. Maybe the new 'E test' or the spiral gradient procedure can be used after evaluation.

  10. Effect of Paullinia cupana on MCF-7 breast cancer cell response to chemotherapeutic drugs.

    PubMed

    Hertz, Everaldo; Cadoná, Francine Carla; Machado, Alencar Kolinski; Azzolin, Verônica; Holmrich, Sabrina; Assmann, Charles; Ledur, Pauline; Ribeiro, Euler Esteves; DE Souza Filho, Olmiro Cezimbra; Mânica-Cattani, Maria Fernanda; DA Cruz, Ivana Beatrice Mânica

    2015-01-01

    Previous studies suggested that certain plants, such as guarana (Paullinia cupana), exert a protective effect against cancer-related fatigue in breast cancer patients undergoing chemotherapy. However, guarana possesses bioactive molecules, such as caffeine and catechin, which may affect the pharmacological properties of antitumor drugs. Therefore, the aim of this study was to evaluate the effects of guarana on breast cancer cell response to 7 chemotherapeutic agents currently used in the treatment of breast cancer. To perform this study, MCF-7 breast cancer cells were cultured under controlled conditions and exposed to 1, 5 and 10 µg/ml guarana concentrations, with and without chemotherapeutics (gemcitabine, vinorelbine, methotrexate, 5-fluorouracil, paclitaxel, doxorubicin and cyclophosphamide). The effect of these treatments on MCF-7 cell viability and proliferation was spectrophotometrically analyzed with the MTT assay. The main results demonstrated an antiproliferative effect of guarana at concentrations of 5 and 10 µg/ml and a significant effect on chemotherapeutic drug action. In general, guarana improved the antiproliferative effect of chemotherapeutic agents, causing a decrease of >40% in cell growth after 72 h of exposure. The results suggested an interaction of guarana with the chemotherapeutic drugs, which requires confirmation by in vivo complementary studies.

  11. Nrf2 inhibition sensitizes cholangiocarcinoma cells to cytotoxic and antiproliferative activities of chemotherapeutic agents.

    PubMed

    Samatiwat, Papavee; Prawan, Auemduan; Senggunprai, Laddawan; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol

    2016-08-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating antioxidant, cytoprotective, and metabolic enzymes, plays important roles in drug resistance and proliferation in cancer cells. The present study was aimed to examine the expression of Nrf2 in connection with chemotherapeutic drug sensitivity on cholangiocarcinoma (CCA) cells. The basal levels of Nrf2 protein in cytosol and nuclear fractions of CCA cells were determined using Western blot analysis. Nrf2 mRNA expression of KKU-M156 and KKU-100 cells, representatives of low and high-Nrf2-expressing CCA cells, were silenced using siRNA. After knockdown of Nrf2, the sensitivity of those cells to the cytotoxicity of cisplatin (Cis) was enhanced in association with the increased release of AIF and downregulation of Bcl-xl in both cells. Also, knockdown of Nrf2 suppressed the replicative capability of those cells in colony-forming assay and enhanced their sensitivity to antiproliferative activity of Cis and 5-fluorouracil. The chemosensitizing effect was associated with the suppressed expression of Nrf2-regulated and Cis-induced antioxidant and metabolic genes including NQO1, HO-1, GCLC, TXN, MRP2, TKT, and G6PD. In cell cycle analysis, Nrf2 knockdown cells were arrested at G0/G1 phase and combination with Cis increased the accumulation of cells at S phase. The suppression of KKU-M156 cell proliferation was associated with the downregulation of cyclin D1 and increased level of p21. Inhibition of Nrf2 could be a novel strategy in enhancing antitumor activity of chemotherapeutic agent in control of resistant cancer.

  12. Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents.

    PubMed

    Cassady, J M; Baird, W M; Chang, C J

    1990-01-01

    Recent advances in the chemistry of novel bioactive natural products are reported. This research is directed to the exploration of plants with confirmed activity in bioassays designed to detect potential cancer chemotherapeutic and chemopreventive agents. Structural work and chemical studies are reported for several cytotoxic agents from the plants Annona densicoma, Annona reticulata, Claopodium crispifolium, Polytrichum obioense, and Psorospermum febrifugum. Studies are also reported based on development of a mammalian cell culture benzo[a]pyrene metabolism assay for the detection of potential anticarcinogenic agents from natural products. In this study a number of isoflavonoids and flavonoids with antimutagenic activity have been discovered.

  13. High-frequency induction of chromosomal rearrangements in mouse germ cells by the chemotherapeutic agent chlorambucil.

    PubMed

    Rinchik, E M; Flaherty, L; Russell, L B

    1993-12-01

    Recent mutagenesis studies have demonstrated that the chemotherapeutic agent, chlorambucil (CHL), is highly mutagenic in male germ cells of the mouse. Post-meiotic germ cells, and especially early spermatids, are the most sensitive to the cytotoxic and mutagenic effects of this agent. Genetic, cytogenetic and molecular analyses of many induced mutations have shown that, in these germ-cell stages, CHL induces predominantly chromosomal rearrangements (deletions and translocations), and mutation-rate studies show that, in terms of tolerated doses, CHL is perhaps five to ten times more efficient in inducing rearrangements than is radiation exposure. Appropriate breeding protocols, along with knowledge of the advantages and limitations associated with the use of CHL, can be used to expand the current resource of chromosomal rearrangements in the mouse and to provide new phenotype-associated mutations amenable to positional-cloning techniques. The analysis of CHL-induced mutations has also contributed to understanding the factors that affect the yield and nature of chemically induced germline mutations in mammals.

  14. Treatment of cancer using pulsed electric field in combination with chemotherapeutic agents or genes.

    PubMed

    Nishi, T; Dev, S B; Yoshizato, K; Kuratsu, J; Ushio, Y

    1997-03-01

    Electroporation is a standard laboratory technique originally developed for in vitro transfer of molecules into cells. It involves application of electrical pulses ranging from micro- to milliseconds that create transient pores in the cell membrane allowing intracellular access of exogenous molecules. This technique has been successfully applied to regress tumors in animal models by combining electroporation with chemotherapeutic agents--a process known as electrochemotherapy (ECT) which substantially enhance cytotoxicity of some antineoplastic agents. Recently ECT has moved into clinical arena and patients with cutaneous tumors and head and neck cancers have been treated very effectively with ECT. Parallel to ECT, a technique has also been developed which makes it possible to inject plasmid DNA and combine it with in vivo electroporation--electro--genetherapy (EGT)--to deliver in a highly efficient manner both marker and functional genes into target tissue and achieve gene expression. Thus, in vivo electroporation is contributing to the development of a new strategy for cancer treatment with both drugs and genes.

  15. Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1

    PubMed Central

    2011-01-01

    Background Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV. Methods Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC). Results H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone. Conclusions In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a

  16. Effect of a novel oral chemotherapeutic agent containing a combination of trifluridine, tipiracil and the novel triple angiokinase inhibitor nintedanib, on human colorectal cancer xenografts

    PubMed Central

    Suzuki, Norihiko; Nakagawa, Fumio; Matsuoka, Kazuaki; Takechi, Teiji

    2016-01-01

    Trifluridine/tipiracil (TFTD) is a combination drug that is used for the treatment of metastatic colorectal cancer and was formerly known as TAS-102. It is a combination of two active pharmaceutical compounds, trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine in vivo. TFTD is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is resistant to standard therapies. In the present study, the anticancer effects of trifluridine in combination with nintedanib, an oral triple angiokinase inhibitor, on human colorectal cancer cell lines were investigated. The cytotoxicity against DLD-1, HT-29, and HCT116 cell lines was determined by the crystal violet staining method. The combination of trifluridine and nintedanib exerted an additive effect on the growth inhibition of DLD-1 and HT-29 cells and a sub-additive effect on HCT116 cells, as determined by isobologram analyses. Subsequently, the human colorectal cancer cell lines were implanted subcutaneously into nude mice to allow the evaluation of the in vivo tumor growth inhibitory effects of TFTD and nintedanib combination therapy. TFTD (150 mg/kg/day) and/or nintedanib (40 mg/kg/day) were orally administered to the mice twice daily from day 1 to day 14. The tumor growth inhibition with combination therapy was 61.5, 72.8, 67.6 and 67.5% for the DLD-1, DLD-1/5-FU, HT-29, and HCT116 xenografts, respectively. This was significantly (P<0.05) higher than the effects of monotherapy with either TFTD or nintedanib. These results demonstrated the effectiveness of the combination of TFTD and nintedanib in the treatment of colorectal cancer xenografts. The concentration of trifluridine incorporated into DNA in the HT-29 and HCT116 tumors was determined by liquid chromatography-tandem mass spectrometry. The incorporation levels following treatment with TFTD and nintedanib for 14 consecutive days were higher than

  17. Chemosensitization of Breast Cancer Cells to Chemotherapeutic Agents by 3,3’diindolylmethane (DIM)

    DTIC Science & Technology

    2006-08-01

    carbinol protects against covalent binding of benzo [ a ] pyrene and N -nitrosodimethylamine metabolites to mouse liver macromolecules. Chem Biol Interact...TκB has been reported to play a role in de novo resistance of cancer cells to chemotherapeutic agents, which is a major cause for treatment failure in... cancer chemotherapy. Previous studies have shown that 3,3’-diindolylmethane (DIM), a major in vivo acid- catalyzed condensation product of Indole-3

  18. Chemosensitization of Breast Cancer Cells to Chemotherapeutic Agents by 3,3’-Diindolylmethane (DIM)

    DTIC Science & Technology

    2007-08-01

    protects against covalent binding of benzo [ a ] pyrene and N -nitrosodimethylamine metabolites to mouse liver macromolecules. Chem Biol Interact 1984;48...by ANSI Std. Z39.18 Constitutive activation of Akt or NF-κB has been reported to play a role in de novo resistance of cancer cells to...chemotherapeutic agents, which is a major cause of treatment failure in cancer chemotherapy. Previous studies have shown that 3, 3’-diindolylmethane (DIM), a

  19. Mechanistic perspectives on cancer chemoprevention/chemotherapeutic effects of thymoquinone.

    PubMed

    Kundu, Juthika; Chun, Kyung-Soo; Aruoma, Okezie I; Kundu, Joydeb Kumar

    2014-10-01

    The bioactive natural products (plant secondary metabolites) are widely known to possess therapeutic value for the prevention and treatment of various chronic diseases including cancer. Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ), a monoterpene present in black cumin seeds, exhibits pleiotropic pharmacological activities including antioxidant, anti-inflammatory, antidiabetic and antitumor effects. TQ inhibits experimental carcinogenesis in a wide range of animal models and has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumors in vivo. The mechanistic basis of anticancer effects of TQ includes the inhibition of carcinogen metabolizing enzyme activity and oxidative damage of cellular macromolecules, attenuation of inflammation, induction of cell cycle arrest and apoptosis in tumor cells, blockade of tumor angiogenesis, and suppression of migration, invasion and metastasis of cancer cells. TQ shows synergistic and/or potentiating anticancer effects when combined with clinically used chemotherapeutic agents. At the molecular level, TQ targets various components of intracellular signaling pathways, particularly a variety of upstream kinases and transcription factors, which are aberrantly activated during the course of tumorigenesis.

  20. Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model.

    PubMed

    League-Pascual, James C; Lester-McCully, Cynthia M; Shandilya, Shaefali; Ronner, Lukas; Rodgers, Louis; Cruz, Rafael; Peer, Cody J; Figg, William D; Warren, Katherine E

    2017-03-13

    The blood-brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1 mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration-time curves for CSF and plasma (AUCCSF:plasma). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32-57) and 22 (20-41)%, respectively. Although maximum TMZ drug concentration in the CSF (Cmax) was lower after intranasal

  1. Synergistic interaction of telomerase-specific oncolytic virotherapy and chemotherapeutic agents for human cancer.

    PubMed

    Fujiwara, Toshiyoshi; Kagawa, Shunsuke; Tazawa, Hiroshi

    2012-07-01

    Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials; data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer.

  2. Dacarbazine in melanoma: from a chemotherapeutic drug to an immunomodulating agent.

    PubMed

    Ugurel, Selma; Paschen, Annette; Becker, Jürgen C

    2013-02-01

    Chemotherapeutic drugs are clinically used to treat cancer because of their cytotoxic activities against tumor cells. Recently, however, evidence is accumulating-including the report of Hervieu et al. (2012) in the current issue of The Journal of Investigative Dermatology-indicating that at least some of these drugs have broader activities and that they should also be considered immunomodulatory agents. Indeed, Hervieu demonstrates that dacarbazine (DTIC) exerts immunostimulatory effects by inducing local activation of natural killer (NK) and T cells, suggesting that upon treatment with DTIC, the tumor participates in the initiation of an immune response: (i) DTIC treatment elicits the expression of ligands of the immunoreceptor NKG2D on melanoma cells; (ii) engagement of the ligands by NKG2D on NK cells leads to their activation, allowing enhanced tumor-cell killing and the release of IFN-γ; and (iii) IFN-γ in turn upregulates major histocompatibility complex class I expression on tumor cells, which favors their recognition by cytotoxic CD8+ T lymphocytes (CTLs).

  3. Long-term consequences of chemotherapeutic agents on hematopoiesis: development of altered radiation tolerance.

    PubMed

    Kovacs, C J; Evans, M J; Hooker, J L; Johnke, R M

    1988-01-01

    The long-term effects of chemotherapeutic agents on subsequent radiation tolerance of the hematopoietic marrow were studied after a single injection of doxorubicin, 5-fluorouracil, or cyclophosphamide at a maximum tolerated dose. At designated intervals following drug treatment, drug-treated and age-matched control male B6D2F1 mice were exposed to 4.5 Gy of total-body irradiation, and the recovery kinetics of the stem cell (assayed at days 8 and 13 colony-forming spleen units) and progenitor (burst-forming erythroid units, and colony-forming erythroid and granulocyte/macrophage units) compartments were established. Response deficits were calculated for each compartment by comparison of treated and control recovery curves at 5 intervals over 32 weeks. Based on these response deficits, a number of conclusions were drawn: 1) There is selective drug specificity for the more primitive (13d) and mature (8d) CFUs subpopulations; 2) these sensitivities determine the temporal consequences of drug treatment on subsequent radiation tolerance in the marrow (e.g., acute, delayed, or long term); and 3) drugs that influence long-term radiation tolerance of the marrow are dose dependent and initially affect the more primitive stem cells. The data suggest that the initial lesion in the stem cell compartment, resulting in long-term enhancement of radiosensitivity, involves a major restriction (either in cell number or in genetic functionality) of the proliferative potential necessary for recovery from subsequent radiation insult.

  4. Genome-Wide Mutational Signature of the Chemotherapeutic Agent Mitomycin C in Caenorhabditis elegans.

    PubMed

    Tam, Annie S; Chu, Jeffrey S C; Rose, Ann M

    2015-11-12

    Cancer therapy largely depends on chemotherapeutic agents that generate DNA lesions. However, our understanding of the nature of the resulting lesions as well as the mutational profiles of these chemotherapeutic agents is limited. Among these lesions, DNA interstrand crosslinks are among the more toxic types of DNA damage. Here, we have characterized the mutational spectrum of the commonly used DNA interstrand crosslinking agent mitomycin C (MMC). Using a combination of genetic mapping, whole genome sequencing, and genomic analysis, we have identified and confirmed several genomic lesions linked to MMC-induced DNA damage in Caenorhabditis elegans. Our data indicate that MMC predominantly causes deletions, with a 5'-CpG-3' sequence context prevalent in the deleted regions of DNA. Furthermore, we identified microhomology flanking the deletion junctions, indicative of DNA repair via nonhomologous end joining. Based on these results, we propose a general repair mechanism that is likely to be involved in the biological response to this highly toxic agent. In conclusion, the systematic study we have described provides insight into potential sequence specificity of MMC with DNA.

  5. Assessment of the significance of mitochondrial DNA damage by chemotherapeutic agents.

    PubMed

    Lo, Soo; Tolner, Berend; Taanman, Jan-Willem; Cooper, J Mark; Gu, Mei; Hartley, John A; Schapira, Anthony H V; Hochhauser, Daniel

    2005-08-01

    The pathways which are activated following damage to nuclear DNA in cancer cells are well understood. There is evidence that treatment with several chemotherapeutic agents may result in damage to mitochondrial DNA. This study investigated the contribution of mitochondrial DNA to cytotoxicity of DNA-interactive agents. To understand the significance of drug interactions with mitochondrial DNA, we investigated A549 non-small cell lung cancer cell lines and their rho0 derivatives in which mitochondrial DNA has been eradicated. The parental cell line showed increased sensitivity to the anthracycline daunorubicin when compared with the A549 rho0 line. In addition, the A549 rho0 line was resistant to the rhodacyanine derivative, MKT-077, which has been shown to interact with mitochondrial DNA. Southern blotting demonstrated that MKT-077 mediated damage to mitochondrial but not nuclear DNA. Restoration of mitochondrial DNA by formation of cybrids restored sensitivity to these agents. The mitochondrial DNA damage, following treatment of A549 rho0 cells with MKT-077, resulted in G2 arrest which was not mediated by expression of p53. Mitochondrial DNA is a critical target for MKT-077 and daunorubicin, and is a potential target for novel chemotherapeutic agents.

  6. Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis.

    PubMed

    Huang, Mei-Yun; Pan, Hao; Liang, Yi-Dan; Wei, Hong-Xia; Xu, Li-Hui; Zha, Qing-Bing; He, Xian-Hui; Ouyang, Dong-Yun

    2016-02-01

    CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.

  7. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy.

    PubMed

    Siemann, Dietmar W; Mercer, Emma; Lepler, Sharon; Rojiani, Amyn M

    2002-05-01

    The utility of combining the vascular targeting agents 5,6-dimethyl-xanthenone-4 acetic acid (DMXAA) and combretastatin A-4 disodium phosphate (CA4DP) with the anticancer drugs cisplatin and cyclophosphamide (CP) was evaluated in experimental rodent (KHT sarcoma), human breast (SKBR3) and ovarian (OW-1) tumor models. Doses of the vascular targeting agents that led to rapid vascular shutdown and subsequent extensive central tumor necrosis were identified. Histologic evaluation showed morphologic damage of tumor cells within a few hours after treatment, followed by extensive hemorrhagic necrosis and dose-dependent neoplastic cell death as a result of prolonged ischemia. Whereas these effects were induced by a range of CA4DP doses (10-150 mg/kg), the dose response to DMXAA was extremely steep; doses < or = 15 mg/kg were ineffective and doses > or = 20 mg/kg were toxic. DMXAA also enhanced the tumor cell killing of cisplatin, but doses > 15 mg/kg were required. In contrast, CA4DP increased cisplatin-induced tumor cell killing at all doses studied. This enhancement of cisplatin efficacy was dependent on the sequence and interval between the agents. The greatest effects were achieved when the vascular targeting agents were administered 1-3 hr after cisplatin. When CA4DP (100 mg/kg) or DMXAA (17.5 mg/kg) were administered 1 hr after a range of doses of cisplatin or CP, the tumor cell kill was 10-500-fold greater than that seen with chemotherapy alone. In addition, the inclusion of the antivascular agents did not increase bone marrow stem cell toxicity associated with these anticancer drugs, thus giving rise to a therapeutic gain.

  8. Tissue levels of chemotherapeutic agents for hepatic metastasis during hepatic arterial and portal injection.

    PubMed

    Kaneko, A; Naomoto, Y; Aoyama, M; Tanaka, N

    1999-01-01

    Hepatic metastasis is one of the most important prognostic factors in digestive organ cancer, and hepatic arterial infusion is aggressively performed for therapy of nonresectable metastatic liver cancer. Although comparatively high response rates have been attained in some cases, this treatment has been ineffective in not a few cases because these metastatic tumors are frequently hypovascular in nature. To develop better methods of administering chemotherapeutic agents, we performed basic experiments concerning intraportal administration which has been regarded as having a generally negative effect, focusing on a report indicating that portal supply is dominant along the borders of metastatic liver cancer tumors. VX2 carcinoma cells were inoculated into the hepatic parenchyma beneath the capsule of juvenile Japanese white rabbits. Drugs were infused 2 weeks after the inoculation, then tissue and blood were sequentially sampled. Mitomycin C (1.7 mg/kg) was infused either by bolus injection to the hepatic artery (arterial infusion group) or by bolus injection to the portal vein (portal infusion group). Five-fluorouracil (9.5 mg/kg) and Cisplatin (1.6 mg/kg) were likewise infused continuously over 60 min, and tissue levels of the drugs were compared between the two groups. Mitomycin C and 5-fluorouracil levels were measured by HPLC and Cisplatin levels were measured by atomic absorption spectrophotometry. As a result, the levels of every drug in VX2 tumor tissue did not significantly differ between the arterial infusion group and the portal infusion group, while the levels were significantly higher than those in the intravenous infusion group. Using portal infusion, we observed a drug transition which was not inferior to that of arterial infusion, suggesting that an imported antitumoral effect may be obtained with this method compared with intravenous infusion.

  9. Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes

    PubMed Central

    Tseng, Yuan-Yun; Yang, Tao-Chieh; Wang, Yi-Chuan; Lee, Wei-Hwa; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2017-01-01

    Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromatography. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of the antiangiogenic combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and anti-angiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration. PMID:28243088

  10. Testing chemotherapeutic agents in the feather follicle identifies a selective blockade of cell proliferation and a key role for sonic hedgehog signaling in chemotherapy-induced tissue damage.

    PubMed

    Xie, Guojiang; Wang, Hangwei; Yan, Zhipeng; Cai, Linyan; Zhou, Guixuan; He, Wanzhong; Paus, Ralf; Yue, Zhicao

    2015-03-01

    Chemotherapeutic agents induce complex tissue responses in vivo and damage normal organ functions. Here we use the feather follicle to investigate details of this damage response. We show that cyclophosphamide treatment, which causes chemotherapy-induced alopecia in mice and man, induces distinct defects in feather formation: feather branching is transiently and reversibly disrupted, thus leaving a morphological record of the impact of chemotherapeutic agents, whereas the rachis (feather axis) remains unperturbed. Similar defects are observed in feathers treated with 5-fluorouracil or taxol but not with doxorubicin or arabinofuranosyl cytidine (Ara-C). Selective blockade of cell proliferation was seen in the feather branching area, along with a downregulation of sonic hedgehog (Shh) transcription, but not in the equally proliferative rachis. Local delivery of the Shh inhibitor, cyclopamine, or Shh silencing both recapitulated this effect. In mouse hair follicles, those chemotherapeutic agents that disrupted feather formation also downregulated Shh gene expression and induced hair loss, whereas doxorubicin or Ara-C did not. Our results reveal a mechanism through which chemotherapeutic agents damage rapidly proliferating epithelial tissue, namely via the cell population-specific, Shh-dependent inhibition of proliferation. This mechanism may be targeted by future strategies to manage chemotherapy-induced tissue damage.

  11. Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.

    PubMed

    Pace, Jennifer R; DeBerardinis, Albert M; Sail, Vibhavari; Tacheva-Grigorova, Silvia K; Chan, Kelly A; Tran, Raymond; Raccuia, Daniel S; Wechsler-Reya, Robert J; Hadden, M Kyle

    2016-04-28

    Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.

  12. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach.

    PubMed

    Lee, Kuo-Hsiung

    2010-03-26

    Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long-term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogues, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analogue synthesis, and structure-activity relationship and mechanism of action studies. Current clinical trial agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called "maturation inhibitors". In addition, an etoposide analogue, GL-331, progressed to anticancer phase II clinical trials, and the curcumin analogue JC-9 is in phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trial candidates will also be discussed.

  13. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    SciTech Connect

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2014-09-24

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  14. Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

    NASA Astrophysics Data System (ADS)

    Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.; Conn, Charlotte E.; Kimpton, Kathleen; Waddington, Lynne J.; Krodkiewska, Irena; Drummond, Calum J.

    2011-03-01

    We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

  15. Interactions of human leukocyte interferon with vinca alkaloids and other chemotherapeutic agents against human tumors in clonogenic assay.

    PubMed

    Aapro, M S; Alberts, D S; Salmon, S E

    1983-01-01

    Purified human leukocyte interferon produced by recombinant techniques (IFN-alpha A) was tested in vitro with chemotherapeutic drugs, vinblastine (VLB), vincristine (VCR), vindesine (VDS), vinzolidine (VZL), cis-platinum (PLAT), doxorubicin (DOXO), etoposide (VP-16), and melphalan (MEL). The activity of these agents alone or in combination was tested against various human tumor cell lines, using a modified soft agar clonogenic assay. Three human tumor cell lines (myeloma, RPMI 8226; breast, MCF-7; and colon, WiDR) showed sensitivity to these agents at clinically achievable drug concentrations. Statistically significant synergistic activity against in vitro colony formation was observed with the combination of VLB and IFN-alpha A. An additive or sub-additive effect was usually observed with the other agents tested. Continuous exposure of the 8226 myeloma cell line to both IFN-alpha A and PLAT showed evidence of a more significant potentiation. It is hypothesized that the synergistic effect observed between VLB and IFN-alpha A is due to some of their common mechanisms of action.

  16. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    PubMed Central

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID:26766908

  17. Antinuclear antibodies with nucleosome-restricted specificity for targeted delivery of chemotherapeutic agents.

    PubMed

    Torchilin, Vladimir P

    2010-08-01

    Circulating antinuclear autoantibodies (ANAs) are well known to accompany various pathological conditions and can be artificially induced by immunization. Research and clinical data permit us to hypothesize a definite connection between cancer and ANAs. Based on the available data, my group's research suggested that exogenous ANAs may be used as anticancer therapeutics. Among these ANAs, nucleosome-specific ANAs may be particularly useful. Advances in cancer immunotherapy with monoclonal antibodies re-emphasized the role of humoral immunity in neoplasia control. The development of a universal antibody targeting diverse cancers is of clear importance. We showed that certain natural ANAs recognize the surface of numerous tumor cells but not normal cells via cell surface-bound nucleosomes originating from the apoptotically dying neighboring tumor cells, mediate antibody-dependent cellular cytotoxicity of tumor cells in vitro and inhibit the development of murine tumor in syngeneic mice. A single monoclonal antinuclear nucleosome-specific autoantibody, mAb 2C5, specifically recognizes multiple unrelated human tumor cell lines and accumulates at a high tumor-to-normal cell ratio in various human tumors in nude mice. Immunotherapy with mAb 2C5 resulted in significant suppression of the growth of several human tumors. In addition, mAb 2C5, when used in subtherapeutic quantities, can serve as a highly efficient specific ligand to target various drug- or diagnostic agent-loaded pharmaceutical nanocarriers, such as liposomes and polymeric micelles, to various tumors. Here, the data (accumulated predominantly in our laboratory over several years) on mAb 2C5-mediated tumor targeting of chemotherapeutic agents is reviewed.

  18. Impairment of stress granule assembly via inhibition of the eIF2alpha phosphorylation sensitizes glioma cells to chemotherapeutic agents.

    PubMed

    Vilas-Boas, Fabrício de Almeida Souza; da Silva, Aristóbolo Mendes; de Sousa, Lirlândia Pires; Lima, Kátia Maciel; Vago, Juliana Priscila; Bittencourt, Lucas Felipe Fernandes; Dantas, Arthur Estanislau; Gomes, Dawidson Assis; Vilela, Márcia Carvalho; Teixeira, Mauro Martins; Barcelos, Lucíola Silva

    2016-04-01

    Malignant gliomas are a lethal type of brain tumors that poorly respond to chemotherapeutic drugs. Several therapy resistance mechanisms have been characterized. However, the response to stress through mRNA translational control has not been evaluated for this type of tumor. A potential target would involve the alpha subunit of eukaryotic translation initiation factor (eIF2α) that leads to assembly of stress granules (SG) which are cytoplasmic granules mainly composed by RNA binding proteins and untranslated mRNAs. We assessed whether glioma cells are capable of assembling SG after exposure to different classes of chemotherapeutic agents through evaluation of the effects of interfering in this process by impairing the eIF2α signaling. C6 and U87MG cells were exposed to bortezomib, cisplatin, or etoposide. Forced expression of a dominant negative mutant of eIF2α (eIF2α(DN)) was employed to block this pathway. We observed that exposure to drugs stimulated SG assembly. This was reduced in eIF2α(DN)-transfected cells and this strategy enhanced chemotherapeutically-induced cell death for all drugs. Our data suggest that SG assembly occurs in glioma cells in response to chemotherapeutic drugs in an eIF2α-dependent manner and this response is relevant for drug resistance. Interfering with eIF2α signaling pathway may be a potential strategy for new co-adjuvant therapies to treat gliomas.

  19. A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells

    PubMed Central

    Wang, Liang; Chan, Judy Y.; Zhou, Xinhua; Cui, Guozhen; Yan, Zhixiang; Wang, Li; Yan, Ru; Di, Lijun; Wang, Yuqiang; Hoi, Maggie P.; Shan, Luchen; Lee, Simon M.

    2016-01-01

    We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity. PMID:27559313

  20. A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells.

    PubMed

    Wang, Liang; Chan, Judy Y; Zhou, Xinhua; Cui, Guozhen; Yan, Zhixiang; Wang, Li; Yan, Ru; Di, Lijun; Wang, Yuqiang; Hoi, Maggie P; Shan, Luchen; Lee, Simon M

    2016-01-01

    We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity.

  1. Liposomal chemotherapeutics.

    PubMed

    Gentile, Emanuela; Cilurzo, Felisa; Di Marzio, Luisa; Carafa, Maria; Ventura, Cinzia Anna; Wolfram, Joy; Paolino, Donatella; Celia, Christian

    2013-12-01

    Currently, six liposomal chemotherapeutics have received clinical approval and many more are in clinical trials or undergoing preclinical evaluation. Liposomes exhibit low toxicity and improve the biopharmaceutical features and therapeutic index of drugs, thereby increasing efficacy and reducing side effects. In this review we discuss the advantages of using liposomes for the delivery of chemotherapeutics. Gemcitabine and paclitaxel have been chosen as examples to illustrate how the performance of a metabolically unstable or poorly water-soluble drug can be greatly improved by liposomal incorporation. We look at the beneficial effects of liposomes in a variety of solid and blood-borne tumors, including thyroid cancer, pancreatic cancer, breast cancer and multiple myeloma.

  2. GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner

    SciTech Connect

    Lin, Tao; Meng, Lingjun; Tsai, Robert Y.L.

    2011-10-22

    Highlights: {yields} Strong synergy between mycophenolic acid (MPA) and 5-FU in MDA-MB-231 cells. {yields} Cell type-dependent synergy between MPA and anti-proliferative agents. {yields} The synergy of MPA on 5-FU is recapitulated by RNA polymerase-I inhibition. {yields} The synergy of MPA on 5-FU requires the expression of nucleostemin. -- Abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.

  3. CHEMICAL AGENTS IN NEOPLASTIC DISEASES—An Evaluation of Chemotherapeutic Substances for Clinical Management

    PubMed Central

    Bierman, Howard R.

    1953-01-01

    The rapid appearance of many new chemical substances which possess some antineoplastic effects has created a complex problem for the practicing physician. These agents which have shown promise in man and lower animals are grouped according to their modes of action. Each substance is discussed thoroughly with regard to its structure, activity, and influence upon the neoplasms of man. Key references are cited, and the practical value of each chemical agent is defined. The proper methods of administration of the compounds recommended for use are carefully described. In addition a section on agents whose therapeutic value has been disproven is also included. ImagesFigure 1. PMID:13009518

  4. Repurposing the FDA-Approved Pinworm Drug Pyrvinium as a Novel Chemotherapeutic Agent for Intestinal Polyposis

    PubMed Central

    Giambelli, Camilla; Fei, Dennis Liang; Han, Lu; Hang, Brian I.; Bai, Feng; Pei, Xin-Hai; Nose, Vania; Burlingame, Oname; Capobianco, Anthony J.; Orton, Darren; Lee, Ethan; Robbins, David J.

    2014-01-01

    Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. PMID:25003333

  5. Modification of in vitro and in vivo BCG cell wall-induced immunosuppression by treatment with chemotherapeutic agents or indomethacin

    SciTech Connect

    DeSilva, M.A.; Wepsic, H.T.; Mizushima, Y.; Nikcevich, D.A.; Larson, C.H.

    1985-04-01

    The in vitro inhibition of spleen cell blastogenesis response and the in vivo enhancement of tumor growth are phenomena associated with BCG cell wall (BCGcw) immunization. What effect treatment with chemotherapeutic agents and the prostaglandin inhibitor indomethacin would have on the in vitro and in vivo responses to BCGcw immunization was evaluated. In vitro blastogenesis studies showed that chemotherapy pretreatment prior to immunization with BCGcw resulted in a restoration of the spleen cell blastogenesis response. In blastogenesis addback studies, where BCGcw-induced irradiated splenic suppressor cells were admixed with normal cells, less inhibition of blastogenesis occurred when spleen cells were obtained from rats that had received the combined treatment of chemotherapy and BCGcw immunization versus only BCGcw immunization. The cocultivation of spleen cells from BCGcw-immunized rats with indomethacin resulted in a 30-40% restoration of the blastogenesis response. In vivo studies showed that BCGcw-mediated enhancement of intramuscular tumor growth of the 3924a ACI rat tumor could be abrogated by either pretreatment with busulfan or mitomycin or by the feeding of indomethacin.

  6. Chemotherapeutics challenges in developing effective treatments for the endemic malarias

    PubMed Central

    Kevin Baird, J.

    2012-01-01

    The endemic malarias threaten the several billion people residing where transmission occurs. Chemotherapeutic strategy pitted against these threats hinges upon species- and stage-specific treatments guided by diagnosis and screening against sometime dangerous contraindications. This approach suits malaria as it occurs among travelers in the developed, non-endemic world. However, limiting treatment to that which diagnosis affirms may not be rational in endemic zones. Most of the endemic malarias remain out of diagnostic reach, either by inaccessibility of the parasite stage, insensitivity of the technology, or unavailability of diagnostic services. The partial and fragmented chemotherapeutic attack of malaria guided by confirmed diagnostics leaves most of the endemic malarias unchallenged. Development of elimination therapy, a single course of treatment aimed at all species and stages, would significantly advance progress against the major killers known collectively as malaria. PMID:24533286

  7. Nanocarrier mediated Delivery of siRNA/miRNA in Combination with Chemotherapeutic Agents for Cancer Therapy: Current Progress and Advances

    PubMed Central

    Gandhi, Nishant S.; Tekade, Rakesh K.; Chougule, Mahavir B.

    2014-01-01

    Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibits drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), Multidrug resistant protein 1(MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. PMID:25204288

  8. Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

    PubMed Central

    Larson, Christopher A.; Manorek, Gerald; Adams, Preston; Howell, Stephen B.

    2012-01-01

    The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61β subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61β was constitutively knocked down in 2008 ovarian cancer cells. Sec61β knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61β KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61β-KD cells was analyzed; ATP7A was found to be 2- to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61β. Sec61β-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61β modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61β on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity. PMID:22710939

  9. Sec61β controls sensitivity to platinum-containing chemotherapeutic agents through modulation of the copper-transporting ATPase ATP7A.

    PubMed

    Abada, Paolo B; Larson, Christopher A; Manorek, Gerald; Adams, Preston; Howell, Stephen B

    2012-09-01

    The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61β subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61β was constitutively knocked down in 2008 ovarian cancer cells. Sec61β knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61β KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61β-KD cells was analyzed; ATP7A was found to be 2- to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61β. Sec61β-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61β modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61β on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity.

  10. Noscapine, a benzylisoquinoline alkaloid, sensitizes leukemic cells to chemotherapeutic agents and cytokines by modulating the NF-kappaB signaling pathway.

    PubMed

    Sung, Bokyung; Ahn, Kwang Seok; Aggarwal, Bharat B

    2010-04-15

    Noscapine, a benzylisoquinoline alkaloid derived from opium, was recently reported to exhibit activity against a variety of cancers through a poorly understood mechanism. Because the transcription factor NF-kappaB has been linked with inflammation, survival, proliferation, invasion, and angiogenesis in tumors, we hypothesized that noscapine mediates its effects by modulating the NF-kappaB activation pathway. We found that noscapine potentiates apoptosis induced by cytokines and chemotherapeutic agents in tumor cells. Noscapine alone suppressed proliferation of human leukemia and myeloma cells and downregulated the constitutive expression of cell survival proteins. Noscapine also abrogated the inducible expression of proteins involved in survival, proliferation, invasion, and angiogenesis, all of which are regulated by NF-kappaB. Noscapine suppressed both inducible and constitutive NF-kappaB activation in tumor cells through inhibition of IkappaB kinase, leading to inhibition of phosphorylation and degradation of IkappaBalpha. Noscapine also suppressed phosphorylation and nuclear translocation of p65, leading to inhibition of NF-kappaB reporter activity induced by various components of the NF-kappaB activation pathway. Activity of the NF-kappaB-containing cyclooxygenase-2 promoter was also inhibited by noscapine. Thus, noscapine inhibits the proliferation of leukemia cells and sensitizes them to tumor necrosis factor and chemotherapeutic agents by suppressing the NF-kappaB signaling pathway.

  11. Enriched environment housing enhances the sensitivity of mouse pancreatic cancer to chemotherapeutic agents.

    PubMed

    Wu, Yufeng; Gan, Yu; Yuan, Hui; Wang, Qing; Fan, Yingchao; Li, Guohua; Zhang, Jian; Yao, Ming; Gu, Jianren; Tu, Hong

    2016-04-29

    Living in an enriched housing environment is an established model of eustress and has been consistently shown to reduce the growth of transplanted tumors, including pancreatic cancer. Here, we further investigate the influence of an enriched environment (EE) on the efficacy of chemotherapy in pancreatic cancer. Male C57BL/6 mice were housed in EE or standard environment (SE) conditions and transplanted with syngeneic Panc02 pancreatic cancer cells. Tumor-bearing mice were treated with 5-fluorouracil (5-FU) or gemcitabine (GEM) to examine their sensitivities to chemotherapy. The results showed that both 5-FU and GEM exerted the dose dependent inhibition of tumor growth. The tumor inhibition rates of low-dose 5-FU and GEM were improved from 17.7% and 23.6% to 46.3% and 49.9% by EE housing. Importantly, tumor cells isolated from the pancreatic cancer xenografts of EE mice had significantly enhanced sensitivities to both 5-FU and GEM (IC50 for 5-FU: 2.8 μM versus 27.3 μM; IC50 for GEM: 0.8 μM versus 5.0 μM). Furthermore, using microarray analyses, we identified the "ATP-binding cassette (ABC) transporter" that was overrepresented among EE-induced down-regulated genes in pancreatic cancer. Particularly, the tumoral expression of ABC transporter A8b (ABCA8b) was confirmed to be significantly decreased by EE. Over-expression of ABCA8b in mouse pancreatic cancer cells led to a marked decrease in the sensitivity to chemotherapeutic drugs both in vitro and in vivo. In conclusion, our data indicate that benign stressful stimulation can synergistically boost the efficiency of chemotherapeutics in pancreatic cancer, which suggests a novel strategy for adjuvant cancer therapy.

  12. Enterobacter and Klebsiella species isolated from fresh vegetables marketed in Valencia (Spain) and their clinically relevant resistances to chemotherapeutic agents.

    PubMed

    Falomir, María Pilar; Rico, Hortensia; Gozalbo, Daniel

    2013-12-01

    Occurrence of antibiotic-resistant pathogenic or commensal enterobacteria in marketed agricultural foodstuffs may contribute to their incorporation into the food chain and constitutes an additional food safety concern. In this work, we have determined the clinically relevant resistances to 11 common chemotherapeutic agents in Enterobacter and Klebsiella isolates from fresh vegetables from various sources (supermarkets and greengrocers' shops in Valencia, Spain). A total of 96 isolates were obtained from 160 vegetables analyzed (50% positive samples): 68 Enterobacter isolates (59 E. cloacae, two E. aerogenes, two E. cancerogenus, one E. gergoviae, and four E. sakazakii, currently Cronobacter spp.), and 28 Klebsiella isolates (19 K. oxytoca and 9 K. pneumoniae). Only seven isolates were susceptible to all agents tested, and no resistances to ceftazidime, ciprofloxacin, gentamicin, and chloramphenicol were detected. Most isolates were resistant to amoxicillin/clavulanic acid (74 [58 Enterobacter and 16 Klebsiella]) or to ampicillin (80 [55/25]). Other resistances were less frequent: nitrofurantoin (13 isolates [12/1]), tetracycline (6 [5/1]), co-trimoxazole (3 [3/0]), cefotaxime (1 [1/0]), and streptomycin (2 [1/1]). Multiresistant isolates to two (56 [41/15]), three (10 E. cloacae isolates), four (one E. cloacae and one K. pneumoniae isolate), and five (two E. cloacae isolates) chemotherapeutic agents were also detected. The presence of potential pathogens points to marketed fresh produce, which often is eaten raw, as a risk factor for consumer health. In addition, these results support the usefulness of these bacterial species as indicators of the spreading of antibiotic resistances into the environment, particularly in the food chain, and suggest their role as carriers of resistance determinants from farms to consumers, which may constitute an additional "silent" food safety concern. Therefore, there is a need to improve the hygienic quality of marketed fresh

  13. Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance

    PubMed Central

    Kwatra, Deep; Venugopal, Anand; Standing, David; Ponnurangam, Sivapriya; Dhar, Animesh; Mitra, Ashim; Anant, Shrikant

    2014-01-01

    Recently we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells towards DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of Multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2 and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy. PMID:24129966

  14. Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats

    PubMed Central

    Rahn, E J; Makriyannis, A; Hohmann, A G

    2007-01-01

    Background and purpose: The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified. Experimental approach: Mechanical hypersensitivity developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same times. Effects of the CB1/CB2 receptor agonist WIN55,212-2, the receptor-inactive enantiomer WIN55,212-3, the CB2-selective agonist (R,S)-AM1241, the opiate agonist morphine and vehicle on chemotherapy-induced neuropathy were evaluated. WIN55,212-2 was administered intrathecally (i.t.) or locally in the hindpaw to identify sites of action. Pharmacological specificity was established using competitive antagonists for CB1 (SR141716) or CB2 receptors (SR144528). Key results: Systemic administration of WIN55,212-2, but not WIN55,212-3, suppressed vincristine-evoked mechanical allodynia. A leftward shift in the dose-response curve was observed following WIN55,212-2 relative to morphine treatment. The CB1 (SR141716) and CB2 (SR144528) antagonists blocked the anti-allodynic effects of WIN55,212-2. (R,S)-AM1241 suppressed vincristine-induced mechanical hypersensitivity through a CB2 mechanism. Both cannabinoid agonists suppressed vincristine-induced mechanical hypersensitivity without inducing catalepsy. Spinal sites of action are implicated in cannabinoid modulation of chemotherapy-induced neuropathy. WIN55,212-2, but not WIN55,212-3, administered i.t. suppressed vincristine-evoked mechanical hypersensitivity at doses that were inactive following local hindpaw administration. Spinal coadministration of both the CB1 and CB2 antagonists blocked the anti-allodynic effects of WIN55,212-2. Conclusions and implications: Cannabinoids suppress the maintenance of vincristine-induced mechanical allodynia through activation of CB1 and CB2 receptors. These anti-allodynic effects

  15. Chemotherapeutic effect of Berberis integerrima hydroalcoholic extract on colon cancer development in the 1,2-dimethyl hydrazine rat model.

    PubMed

    Malayeri, Mohammad R Mohammadi; Dadkhah, Abolfazl; Fatemi, Faezeh; Dini, Salome; Torabi, Fatemeh; Tavajjoh, Mohammad M; Rabiei, Javad

    The aim of this study was to investigate the efficacy of a Berberis integerrima hydroalcoholic extract as a chemotherapeutic agent in colon carcinogenesis in the rat induced by 1,2-dimethyl hydrazine (DMH). Male Wistar rats were divided into five groups: a negative control group without DMH treatment; a control group injected DMH (20 mg/kg b.w); two groups receiving B. integerrima extract (50 and 100 mg/kg b.w), concomitant with injected DMH, as chemotherapeutic groups; a positive control group receiving 5-fluorouracil (5-FU) along with DMH. The effects of the extracts were determined by assessment of hepatic malondialdehyde (MDA), glutathione (GSH), ferric reducing ability of plasma (FRAP), and the activities of hepatic glutathione S-transferase and cytochrome P450 (GST and CYP450). Additionally, colon tissues were assessed for colonic β-catenin and histopathological analysis. In DMH-treated rats, the extracts partially normalized the levels of FRAP, CYP450, β-catenin, and GST. Likewise, formation of aberrant crypt foci (ACF) in colon tissue of DMH-treated was reduced by the extracts. Thus, the extracts possess chemotherapeutic activity against colon carcinogenesis.

  16. The Effect of Chemotherapeutic Agents on Immune Reactions.

    DTIC Science & Technology

    1982-08-01

    Tween - 80 in saline. The drugs were first . ... p. p-𔃾 dissolved in methylcellulose- Tween - 80 mixture and then diluted to the exact concentration with...Control mice received 0.4 ml solvent (methyl- cellulose- Tween - 80 in saline). Drugs were injected one day before or one day after the antigei for the

  17. A New Chemotherapeutic Investigation: Piracetam Effects on Dyslexia.

    ERIC Educational Resources Information Center

    Chase, Christopher H.; Schmitt, R. Larry

    1984-01-01

    Compared to placebo controls, 28 individuals treated with Piracetam (a new drug thought to enhance learning and memory consolidation) showed statistically significant improvements above baseline scores on measures of effective reading accuracy and comprehension, reading speed, and writing accuracy. The medication was well tolerated and showed no…

  18. Chemotherapeutic effects of bioassay-guided extracts of the American cockroach, Periplaneta americana.

    PubMed

    Wang, Xiao-Yu; He, Zheng Chun; Song, Li-Yan; Spencer, Shawn; Yang, Lei Xiang; Peng, Fang; Liu, Guang-Ming; Hu, Ming-Hui; Li, Hai Bo; Wu, Xiu-Mei; Zeng, Su; Hilgenfeld, Rolf; Stöckigt, Joachim; Zhao, Yu; Qian, Jin Fu

    2011-09-01

    The organic extract of Periplaneta americana L. (Dictyoptera; Blattidae) has been traditionally used in southwestern China as an alternative medicine against disorders such as hepatitis, trauma, gastric ulcers, burns, and heart disease. The present study describes bioassay-guided purification and chemotherapeutic evaluation of the 60% ethanolic fraction of P americana organic extracts (PAE60). The most effective cytotoxic fraction was determined by way of repeated in vitro screenings against 12 distinct cultured human carcinoma cell lines: Eca 109, BGC823, HO8910, LS174T, CNE, HeLa, K562, PC-3, A549, BEL 7404, HL-60, and KB, followed by in vivo antitumor assays of the lead fraction (PAE60). The complexity of enriched active fraction was qualitatively evaluated using thin layer chromatography. Reconstituted PAE60 was effective at inhibiting HL-60, KB, CNE, and BGC823 cell growth with IC(50) values <20 µg mL-(1). PAE60 reduced tumor growth in S180-bearing immunocompetent mice by 72.62% after 10 days following oral doses of 500 mg kg d-(1) compared with 78.75% inhibition following 40 mg kg d-(1) of cyclophosphamide (CTX). Thymus and spleen indices of S180-bearing mice treated with PAE60 were significantly greater (P < .05) than CTX treatment groups, suggesting potential immunomodulation of antitumor host defenses by PAE60. Antiviral activity was also investigated and PAE60 inhibited herpes simplex type-2 replication (IC(50) = 4.11 ± 0.64 µg mL-(1)) with a selectivity index (CC(50) to IC(50) ratio) of 64.84 in Vero cells but was less effective on type-1 virus (IC(50) of 25.6 ± 3.16 µg mL-(1)). These results support future clinical trials on P. americana as an alternative or complementary medicinal agent.

  19. Enhanced X ray sensitivity of human colon tumor cells by combination of N-methylformamide with chemotherapeutic agents

    SciTech Connect

    Leith, J.T.; Lee, E.S.; Leite, D.V.; Glicksman, A.S.

    1986-08-01

    The responses of human colon tumor cells (clone A) to graded doses of x-irradiation were studied in combination with conventional chemotherapeutic drugs (bleomycin and 5-fluorouracil) after induction of commitment to differentiation by chronic exposure to N-methylformamide (NMF). NMF treated cells show increased radiation sensitivity, particularly in the low dose region of the survival curve. When doses of bleomycin (Bleo) and 5-fluorouracil (5-FU) were used that were subtoxic, both agents enhanced the cytotoxicity of x-irradiation by factors of about 1.25 and 1.10, respectively (at the 10% level of survival), and little sequence dependence was seen. However, in NMF treated cells, the combination of these drugs produced enhancement of X ray killing by factors of about 1.6 (x + bleo), 2.5 (bleo + x), 1.4 (x + 5-FU), and 1.6 (5-FU + x). Drug exposures were for 1 hr duration at 37/sup 0/C; 0.05 microgram/ml for Bleo, and 20 micrograms/ml for 5-FU. Since the X ray dose enhancement factor for NMF alone was about 1.3, the increased toxicity seen is probably additive in nature for the NMF + 5-FU + x experiments, but more than additive for the NMF + Bleo + x experiments. Also, complete removal of the shoulder was seen in the NMF + Bleo + X ray experiments. These data indicate that the use of differentiation-inducing agents in combination with other cytotoxic therapies might be important in yielding major decreases in the neoplastic cell burden, while avoiding the major morbidity seen in aggressive cancer therapy.

  20. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

    PubMed Central

    Thys, Ryan G.; Lehman, Christine E.; Pierce, Levi C.T.

    2016-01-01

    Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The distribution of breakpoints by exposure to non-cytotoxic levels of chemicals showed a similar pattern to fusion breakpoints in leukemia patients. Our findings demonstrate that HSPCs exposed to non-cytotoxic levels of environmental chemicals and chemotherapeutic agents are prone to topoisomerase II-mediated DNA damage at the leukemia-associated genes MLL and CBFB. These data suggest a role for long-term environmental chemical or residual

  1. Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells.

    PubMed

    Thys, Ryan G; Lehman, Christine E; Pierce, Levi C T; Wang, Yuh-Hwa

    2015-09-01

    Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The distribution of breakpoints by exposure to non-cytotoxic levels of chemicals showed a similar pattern to fusion breakpoints in leukemia patients. Our findings demonstrate that HSPCs exposed to non-cytotoxic levels of environmental chemicals and chemotherapeutic agents are prone to topoisomerase II-mediated DNA damage at the leukemia-associated genes MLL and CBFB. These data suggest a role for long-term environmental chemical or residual

  2. How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient.

    PubMed

    Hansen, Elsa; Woods, Robert J; Read, Andrew F

    2017-02-01

    When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence-and when it can be bettered.

  3. How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient

    PubMed Central

    Hansen, Elsa; Woods, Robert J.

    2017-01-01

    When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence—and when it can be bettered. PMID:28182734

  4. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention

    PubMed Central

    Grisold, Wolfgang; Cavaletti, Guido; Windebank, Anthony J.

    2012-01-01

    Peripheral neuropathies induced by chemotherapy (CIPN) are an increasingly frequent problem. Contrary to hema­tologic adverse effects, which can be treated with hematopoetic growth factors, neither prophylaxis nor spe­cific treatment is available, and only symptomatic treatment can be offered. Neurotoxic drugs are becoming a major dose-limiting factor. The epidemiology is still unclear. Several drug-dependent pathogenetic mechanisms exist. CIPN are predominately sensory, length-dependent neuropathies that develop after a typical cumulative dose. Usually, the appearance of CIPN is dose dependent, although in at least 2 drugs (oxaliplatin and taxanes), immediate toxic effects occur. The most frequent substances causing CIPN are platin compounds, vinka alkaloids, taxanes, and bortezomib and thalidomide. The role of synergistic neurotoxicity caused by previously given chemo­therapies and concomitant chemotherapies and the role pre-existent neuropathy on the development of a CIPN is not clear. As the number of long-term cancer survivors increases and a new focus on long-term effects of chemotherapy-induced neuropathies emerge, concepts of rehabili­tation need to be implemented to improve the patients’ functions and quality of life. PMID:23095830

  5. In-vitro susceptibility of Giardia lamblia to albendazole, mebendazole and other chemotherapeutic agents.

    PubMed

    Cedillo-Rivera, R; Muñoz, O

    1992-09-01

    The susceptibility of a strain of Giardia lamblia to benzimidazole carbamates, 5-nitroimidazoles, nitrofurans and other drugs was studied in vitro. Albendazole was the most active compound, with a 50% inhibitory concentration (IC50) of 0.01 mg/L and a minimal lethal concentration (MLC) of less than 0.04 mg/L; the IC50 of mebendazole was 0.06 mg/L and the MLC less than 0.5 mg/L. Among the 5-nitroimidazoles tested, ornidazole was the most effective (IC50 0.12 mg/L); tinidazole, metronidazole, secnidazole and hemezole were less active. Nifuroxazide, etofamide and nalidixic acid exhibited modest anti-giardial activity; quinfamide did not inhibit the growth of the parasite at a concentration of 200 mg/L. Albendazole and mebendazole are promising candidates for clinical use and should be further evaluated.

  6. Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles

    PubMed Central

    Han, Yingchao; He, Zhijian; Schulz, Anita; Bronich, Tatiana K.; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V.

    2012-01-01

    Many effective drugs for cancer treatment are poorly water-soluble. In combination chemotherapy, needed excipients in additive formulations are often toxic and restrict their applications in clinical intervention. Here, we report on amphiphilic poly(2-oxazoline)s (POx) micelles as a promising high capacity delivery platform for multi-drug cancer chemotherapy. A variety of binary and ternary drugs combinations of paclitaxel (PTX), docetaxel (DTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), etoposide (ETO) and bortezomib (BTZ) were solubilized in defined polymeric micelles achieving unprecedented high total loading capacities of up to 50 wt.% drug per final formulation. Multi-drug loaded POx micelles showed enhanced stability in comparison to single-drug loaded micelles. Drug ratio dependent synergistic cytotoxicity of micellar ETO/17-AAG was observed in MCF-7 cancer cells and of micellar BTZ/17-AAG in MCF-7, PC3, MDA-MB-231 and HepG2 cells. PMID:22681126

  7. Identification of lead chemotherapeutic agents from medicinal plants against blood flukes and whipworms

    PubMed Central

    Wangchuk, Phurpa; Giacomin, Paul R.; Pearson, Mark S.; Smout, Michael J.; Loukas, Alex

    2016-01-01

    Schistosomiasis and trichuriasis are two of the most common neglected tropical diseases (NTD) that affect almost a billion people worldwide. There is only a limited number of effective drugs to combat these NTD. Medicinal plants are a viable source of parasiticides. In this study, we have investigated six of the 19 phytochemicals isolated from two Bhutanese medicinal plants, Corydalis crispa and Pleurospermum amabile, for their anthelmintic properties. We used the xWORM technique and Scanning Electron Microscope-based imaging to determine the activity of the compounds. Of the six compounds tested, isomyristicin and bergapten showed significant anthelmintic activity against Schistosoma mansoni and Trichuris muris with bergapten being the most efficacious compound one against both parasites (S. mansoni IC50 = 8.6 μg/mL and T. muris IC50 = 10.6 μg/mL) and also against the schistosomulum stage of S. mansoni. These two compounds induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. The efficacy against multiple phylogenetically distinct parasites and different life stages, especially the schistosomulum where praziquantel is ineffective, makes isomyristicin and bergapten novel scaffolds for broad-spectrum anthelmintic drug development that could be used for the control of helminths infecting humans and animals. PMID:27572696

  8. Identification of lead chemotherapeutic agents from medicinal plants against blood flukes and whipworms.

    PubMed

    Wangchuk, Phurpa; Giacomin, Paul R; Pearson, Mark S; Smout, Michael J; Loukas, Alex

    2016-08-30

    Schistosomiasis and trichuriasis are two of the most common neglected tropical diseases (NTD) that affect almost a billion people worldwide. There is only a limited number of effective drugs to combat these NTD. Medicinal plants are a viable source of parasiticides. In this study, we have investigated six of the 19 phytochemicals isolated from two Bhutanese medicinal plants, Corydalis crispa and Pleurospermum amabile, for their anthelmintic properties. We used the xWORM technique and Scanning Electron Microscope-based imaging to determine the activity of the compounds. Of the six compounds tested, isomyristicin and bergapten showed significant anthelmintic activity against Schistosoma mansoni and Trichuris muris with bergapten being the most efficacious compound one against both parasites (S. mansoni IC50 = 8.6 μg/mL and T. muris IC50 = 10.6 μg/mL) and also against the schistosomulum stage of S. mansoni. These two compounds induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. The efficacy against multiple phylogenetically distinct parasites and different life stages, especially the schistosomulum where praziquantel is ineffective, makes isomyristicin and bergapten novel scaffolds for broad-spectrum anthelmintic drug development that could be used for the control of helminths infecting humans and animals.

  9. Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death

    PubMed Central

    Paradisi, Andrea; Creveaux, Marion; Gibert, Benjamin; Devailly, Guillaume; Redoulez, Emeline; Neves, David; Cleyssac, Elsa; Treilleux, Isabelle; Klein, Christian; Niederfellner, Gerhard; Cassier, Philippe A; Bernet, Agnès; Mehlen, Patrick

    2013-01-01

    The secreted factor netrin-1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin-1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin-1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5-Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin-1 expression which is accompanied by netrin-1 receptors increase. This netrin-1 upregulation which appears to be p53-dependent is a survival mechanism as netrin-1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin-1/netrin-1 receptors interactions potentiate Doxorubicin, Cisplatin or 5-Fluorouracil-induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin-1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin-1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin-1 interference could be a promising therapeutic approach. PMID:24293316

  10. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma.

    PubMed

    Veytsman, Irina; Nieman, Lynnette; Fojo, Tito

    2009-09-20

    Adrenal cortical carcinoma (ACC) is a rare malignancy in which patients have poor overall 5-year survival. Patients with ACC can present with symptoms of hormone excess, including Cushing's syndrome, virilization, feminization, or--less frequently--hypertension with hypokalemia. In many patients with ACC, advanced disease at presentation precludes surgery or is followed by local relapse or distant metastatic disease that cannot be managed surgically. In these instances, chemotherapy is often tried, but its limited efficacy all too often leaves the problem of persistent hormonal excess. Physicians who treat patients with ACC and severe hypercortisolism should recognize that uncontrolled hormone production is a malignant disease, which has severe consequences that require aggressive management. Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is administered. Diligent management with frequent adjustments is required, especially in patients with chemotherapy-refractory tumors that continue to grow. In the absence of randomized, controlled trials, adjuvant use of mitotane remains controversial, although the authors of a recent case-control study argue for its use. Despite difficulty administering effective doses, most clinicians agree that mitotane should be used if the tumor cannot be removed surgically or should be used as adjuvant therapy if there is a high likelihood of recurrence. The option of long-term monotherapy is restricted to patients who tolerate mitotane and either experience a clinical response or are at high risk for recurrence. Recommendations are provided to help manage patients with this difficult disease and to improve the quality of their lives.

  11. Targeting pyrimidine pathway of Plasmodium knowlesi: new strategies towards identification of novel antimalarial chemotherapeutic agents.

    PubMed

    Rashmi, Mayank; Yadav, Manoj Kumar; Swati, D

    2017-03-15

    Plasmodium knowlesi has been recently recognized as a human malarial parasite, particularly in the region of south-east Asia. The effective prevention and treatment of this disease is increasingly bound to fail due to the emergence of drug resistance. Hence, design of new drugs against known targets is gaining importance. Pyrimidine pathway is a crucial metabolic pathway in P. knowlesi, and the enzymes involved are also unique in terms of their structure and function as compared to its human counterpart. Thus targeting Dihydroorotase, an enzyme involved in the pyrimidine pathway, provides a promising route for novel drug development. The 3D structure of P. knowlesi Dihydroorotase is not available. The structural homologues of the enzyme are not available in the database, so a threading approach is used to predict the structure. The steric clashes of the predicted model are removed by running a MD simulation of 20 ns. Then the resulting structure is validated by using Ramachandran plot and G-factor analysis. The active sites are predicted and they show interactions with His13, His15, Asp256, Lys97, His134 and His169 for two Zn atoms, and Arg17, Asn42, Thr43, Pro100, His260 and Lys271 for the Dihydroorotate. Interactions between the ligand and binding pocket residues are extracted to create a structure-based pharmacophore model of the docked complex. A four point based pharmacophore model, with four H-bond acceptors and one negative carboxyl ion, was used as a 3D query for screening against 2,664,779 standard lead compounds, obtained from freely available ZINC database. Top 15 compounds with higher pharmacophore-fit score were considered for further study. Among these, only four compounds show desired drug-like properties, and follow the Lipinski's rule of five. Two compounds (ZINC22066495, ZINC20136046) that are negatively charged are found to be more suitable for interaction with positively charged active site of enzyme. Molecular dynamics simulation is used to

  12. Determination of six chemotherapeutic agents in municipal wastewater using online solid-phase extraction coupled to liquid chromatography-tandem mass spectrometry.

    PubMed

    Rabii, Farida W; Segura, Pedro A; Fayad, Paul B; Sauvé, Sébastien

    2014-07-15

    Due to the increased consumption of chemotherapeutic agents, their high toxicity, carcinogenicity, their occurrence in the aquatic environment must be properly evaluated. An analytical method based on online solid-phase extraction coupled to liquid chromatography-tandem mass spectrometry was developed and validated. A 1 mL injection volume was used to quantify six of the most widely used cytotoxic drugs (cyclophosphamide, gemcitabine, ifosfamide, methotrexate, irinotecan and epirubicin) in municipal wastewater. The method was validated using standard additions. The validation results in wastewater influent had coefficients of determination (R(2)) between 0.983 and 0.998 and intra-day precision ranging from 7 to 13% (expressed as relative standard deviation %RSD), and from 9 to 23% for inter-day precision. Limits of detection ranged from 4 to 20 ng L(-1) while recovery values were greater than 70% except for gemcitabine, which is the most hydrophilic compound in the selected group and had a recovery of 47%. Matrix effects were interpreted by signal suppression and ranged from 55 to 118% with cyclophosphamide having the highest value. Two of the target anticancer drugs (cyclophosphamide and methotrexate) were detected and quantified in wastewater (effluent and influent) and ranged from 13 to 60 ng L(-1). The proposed method thus allows proper monitoring of potential environmental releases of chemotherapy agents.

  13. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

    PubMed

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul

    2016-08-01

    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies.

  14. Induction of immunogenic cell death by chemotherapeutic platinum complexes.

    PubMed

    Wong, Daniel Yuan Qiang; Ong, Wendy Wei Fang; Ang, Wee Han

    2015-05-26

    There is compelling evidence suggesting that the immune-modulating effects of many conventional chemotherapeutics, including platinum-based agents, play a crucial role in achieving clinical response. One way in which chemotherapeutics can engage a tumor-specific immune response is by triggering an immunogenic mode of tumor cell death (ICD), which then acts as an "anticancer vaccine". In spite of being a mainstay of chemotherapy, there has not been a systematic attempt to screen both existing and upcoming Pt agents for their ICD ability. A library of chemotherapeutically active Pt agents was evaluated in an in vitro phagocytosis assay, and no correlation between cytotoxicity and phagocytosis was observed. A Pt(II) N-heterocyclic carbene complex was found to display the characteristic hallmarks of a type II ICD inducer, namely focused oxidative endoplasmic reticulum (ER) stress, calreticulin exposure, and both HMGB1 and ATP release, and thus identified as the first small-molecule immuno-chemotherapeutic agent.

  15. Using Agent-Based Modelling to Predict the Role of Wild Refugia in the Evolution of Resistance of Sea Lice to Chemotherapeutants.

    PubMed

    McEwan, Gregor F; Groner, Maya L; Fast, Mark D; Gettinby, George; Revie, Crawford W

    2015-01-01

    A major challenge for Atlantic salmon farming in the northern hemisphere is infestation by the sea louse parasite Lepeophtheirus salmonis. The most frequent method of controlling these sea louse infestations is through the use of chemical treatments. However, most major salmon farming areas have observed resistance to common chemotherapeutants. In terrestrial environments, many strategies employed to manage the evolution of resistance involve the use of refugia, where a portion of the population is left untreated to maintain susceptibility. While refugia have not been deliberately used in Atlantic salmon farming, wild salmon populations that migrate close to salmon farms may act as natural refugia. In this paper we describe an agent-based model that explores the influence of different sizes of wild salmon populations on resistance evolution in sea lice on a salmon farm. Using the model, we demonstrate that wild salmon populations can act as refugia that limit the evolution of resistance in the sea louse populations. Additionally, we demonstrate that an increase in the size of the population of wild salmon results in an increased effect in slowing the evolution of resistance. We explore the effect of a population fitness cost associated with resistance, finding that in some cases it substantially reduces the speed of evolution to chemical treatments.

  16. Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia.

    PubMed

    Boulos, Nidal; Mulder, Heather L; Calabrese, Christopher R; Morrison, Jeffrey B; Rehg, Jerold E; Relling, Mary V; Sherr, Charles J; Williams, Richard T

    2011-03-31

    The introduction of cultured p185(BCR-ABL)-expressing (p185+) Arf (-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome-positive (Ph(+)) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph(+) ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I "gatekeeper" mutations resistant to all 3 Food and Drug Administration-approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non-tumor-cell-autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of "conventional" chemotherapeutic agents with alternate antileukemic mechanisms of action.

  17. Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression

    SciTech Connect

    McDonald, Gail T.; Sullivan, Richard; Pare, Genevieve C.; Graham, Charles H.

    2010-11-15

    Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G{sub 1} phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21{sup Waf1/Cip1} and p27{sup Kip1}; and knockdown of p27{sup kip1} with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity.

  18. Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

    PubMed Central

    SARIN, HEMANT

    2016-01-01

    For proper determination of the apoptotic potential of chemoxenobiotics in synergism, it is important to understand the modes, levels and character of interactions of chemoxenobiotics with cells in the context of predicted conserved biophysical properties. Chemoxenobiotic structures are studied with respect to atom distribution over molecular space, the predicted overall octanol-to-water partition coefficient (Log OWPC; unitless) and molecular size viz a viz van der Waals diameter (vdWD). The Log OWPC-to-vdWD (nm−1) parameter is determined, and where applicable, hydrophilic interacting moiety/core-to-vdWD (nm−1) and lipophilic incorporating hydrophobic moiety/core-to-vdWD (nm−1) parameters of their part-structures are determined. The cellular and sub-cellular level interactions of the spectrum of xenobiotic chemotherapies have been characterized, for which a classification system has been developed based on predicted conserved biophysical properties with respect to the mode of chemotherapeutic effect. The findings of this study are applicable towards improving the effectiveness of existing combination chemotherapy regimens and the predictive accuracy of personalized cancer treatment algorithms as well as towards the selection of appropriate novel xenobiotics with the potential to be potent chemotherapeutics for dendrimer nanoparticle-based effective transvascular delivery. PMID:26998284

  19. 1,3-Bis(2-chloroethyl)-1-nitrosourea-loaded bovine serum albumin nanoparticles with dual magnetic resonance–fluorescence imaging for tracking of chemotherapeutic agents

    PubMed Central

    Wei, Kuo-Chen; Lin, Feng-Wei; Huang, Chiung-Yin; Ma, Chen-Chi M; Chen, Ju-Yu; Feng, Li-Ying; Yang, Hung-Wei

    2016-01-01

    To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM−1 s−1, which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM−1 s−1). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy. PMID:27601895

  20. Linifanib (ABT-869) Potentiates the Efficacy of Chemotherapeutic Agents through the Suppression of Receptor Tyrosine Kinase-Mediated AKT/mTOR Signaling Pathways in Gastric Cancer

    PubMed Central

    Chen, Jing; Guo, Jiawei; Chen, Zhi; Wang, Jieqiong; Liu, Mingyao; Pang, Xiufeng

    2016-01-01

    Gastric cancer, highly dependent on tumor angiogenesis, causes uncontrolled lethality, in part due to chemoresistance. Here, we demonstrate that linifanib (ABT-869), a novel multi-targeted receptor tyrosine kinase inhibitor, markedly augments cytotoxicity of chemotherapies in human gastric cancer. ABT-869 and chemotherapeutic agents exhibited a strong synergy to inhibit the viability of several gastric cancer cell lines, with combination index values ranging from 0.017 to 0.589. Additionally, the combination of ABT-869 and chemotherapeutic agents led to remarkable suppression of vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo. Importantly, in a preclinical gastric cancer xenograft mouse model, drug co-treatments led to increased mouse survival as well as a synergistic reduction in tumor size and the inhibition of tumor angiogenesis. Mechanistic studies further revealed that all of the co-treatments containing ABT-869 resulted in decreased activation of the VEGF receptor, the epidermal growth factor receptor and the insulin growth factor receptor. Inhibition of these receptor tyrosine kinases consequently attenuated the activation of the downstream AKT/mTOR signaling pathway both in cultured gastric cancer cells and in gastric cancer xenografts. Collectively, our findings suggest that the addition of ABT-869 to traditional chemotherapies may be a promising strategy for the treatment of human gastric cancer. PMID:27387652

  1. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species

    PubMed Central

    Ruefli, Astrid A.; Ausserlechner, Michael J.; Bernhard, David; Sutton, Vivien R.; Tainton, Kellie M.; Kofler, Reinhard; Smyth, Mark J.; Johnstone, Ricky W.

    2001-01-01

    Many chemotherapeutic agents induce mitochondrial-membrane disruption to initiate apoptosis. However, the upstream events leading to drug-induced mitochondrial perturbation have remained poorly defined. We have used a variety of physiological and pharmacological inhibitors of distinct apoptotic pathways to analyze the manner by which suberoylanilide hydroxamic acid (SAHA), a chemotherapeutic agent and histone deacetylase inhibitor, induces cell death. We demonstrate that SAHA initiates cell death by inducing mitochondria-mediated death pathways characterized by cytochrome c release and the production of reactive oxygen species, and does not require the activation of key caspases such as caspase-8 or -3. We provide evidence that mitochondrial disruption is achieved by means of the cleavage of the BH3-only proapoptotic Bcl-2 family member Bid. SAHA-induced Bid cleavage was not blocked by caspase inhibitors or the overexpression of Bcl-2 but did require the transcriptional regulatory activity of SAHA. These data provide evidence of a mechanism of cell death mediated by transcriptional events that result in the cleavage of Bid, disruption of the mitochondrial membrane, and production of reactive oxygen species to induce cell death. PMID:11535817

  2. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin

    PubMed Central

    Pang, Baoxu; Qiao, Xiaohang; Janssen, Lennert; Velds, Arno; Groothuis, Tom; Kerkhoven, Ron; Nieuwland, Marja; Ovaa, Huib; Rottenberg, Sven; van Tellingen, Olaf; Janssen, Jeroen; Huijgens, Peter; Zwart, Wilbert; Neefjes, Jacques

    2013-01-01

    DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy. PMID:23715267

  3. Anti-tubercular and antioxidant activities of C-glycosyl carbonic anhydrase inhibitors: towards the development of novel chemotherapeutic agents against Mycobacterium tuberculosis.

    PubMed

    Zaro, María J; Bortolotti, Ana; Riafrecha, Leonardo E; Concellón, Analía; Morbidoni, Héctor R; Colinas, Pedro A

    2016-12-01

    During the treatment of tuberculosis infection, oxidative stress due to anti-tubercular drugs may result in tissue inflammation. It was suggested that treatment with antioxidant drugs could be beneficial as an adjunct to anti-tuberculosis drug therapy. Recently our group has shown that several C-glycosides are inhibitors of Mycobacterium tuberculosis β-carbonic anhydrases (CAs, EC 4.2.1.1). In an effort to develop novel chemotherapeutic agents against tuberculosis, the anti-tubercular and antioxidant activities of a series of C-glycosides containing the phenol or the methoxyaryl moiety were studied. Many compounds showed inhibition of growth of M. tuberculosis H37Rv strain and good antioxidant ability. A glycomimetic incorporating the 3-hydroxyphenyl moiety showed the best activity profile and therefore this functionality represents lead for the development of novel anti-tubercular agents with dual mechanisms of action.

  4. Inhibition of DNA helicase, ATPase and DNA-binding activities of E. coli RecQ helicase by chemotherapeutic agents.

    PubMed

    Zhang, Bo; Zhang, Ai-hua; Chen, Lei; Xi, Xu Guang

    2008-06-01

    RecQ helicases play an essential role in maintaining genetic integrity in all organisms from Escherichia coli to humans. Defects to these enzymes are responsible for three distinct human diseases: Werner syndrome, Bloom syndrome and Rothmund-Thomson syndrome. All three diseases are characterized by a predisposition to cancer due to increased genomic instability. Previous studies on the effects of non-covalent DNA modifications on the catalytic activity of purified Werner and Bloom DNA helicases have shown that both enzymes have similar sensitivity profiles to these DNA-binding agents and are most strongly inhibited by the minor groove binder distamycin A. In this study, we show that the sensitivity profiles of E. coli RecQ to a number of DNA-binding ligands are different to those observed for WRN and Bloom helicases. These observations may give insights into the differences in molecular mechanisms underlying efficient motor function of RecQ helicases.

  5. Ethanol Extract of Oldenlandia diffusa – an Effective Chemotherapeutic for the Treatment of Colorectal Cancer in Humans

    PubMed Central

    Lee, Soojin; Shim, Ji Hwan; Gim, Huijin; Park, Hyun Soo

    2016-01-01

    Objectives: Oldenlandia diffusa is traditionally used to relieve the symptoms of and to treat various diseases, but its anti-cancer activity has not been well studied. In the present study, the authors investigated the anti-cancer effects of an ethanol extract of Oldenlandia diffusa (EOD) on HT-29 human adenocarcinoma cells. Methods: Cells were treated with different concentrations of an EOD, and cell death was assessed by using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Analyses of the sub G1 peak, the caspase-3 and -9 activities, and the mitochondrial membrane depolarizations were conducted to confirm cell death by apoptosis. Also, intracellular reactive oxygen species (ROS) generation was determined using carboxy-H2DCFDA (5-(and-6)-carboxy-20,70-dichlorodihydrofluorescein diacetate). Results: EOD inhibited the proliferation of HT-29 cells for 24 hours by 78.6% ± 8.1% at 50 μg/mL, 74.4% ± 4.6% at 100 μg/mL, 65.9% ± 5.2% at 200 μg/mL, 51.4% ± 6.2% at 300 μg/mL, and by 41.7% ± 8.9% at 400 μg/mL, and treatment for 72 hours reduced the proliferation at the corresponding concentrations by 43.3% ± 8.8%, 24.3 ± 5.1 mV, 13.5 ± 3.2 mV, 6.5 ± 2.3 mV, and by 2.6 ± 2.3 mV. EOD increased the number of cells in the sub-G1 peak in a dose-dependent manner. The mitochondrial membrane depolarization was elevated by EOD. Also, caspase activities were dose-dependently elevated in the presence of EOD, and these activities were repressed by a pan-caspase inhibitor (zVAD-fmk). The ROS generation was significantly increased by EOD and N-acetyl-L-cysteine (NAC; a ROS scavenger) remarkably abolished EOD-induced cell death. In addition, a combination of sub-optimal doses of EOD and chemotherapeutic agents noticeably suppressed the growth of HT-29 cancer cells. Conclusion: These results indicate that EOD might be an effective chemotherapeutic for the treatment of human colorectal cancer. PMID:27280050

  6. Evaluation of uttroside B, a saponin from Solanum nigrum Linn, as a promising chemotherapeutic agent against hepatocellular carcinoma

    PubMed Central

    Nath, Lekshmi R.; Gorantla, Jaggaiah N.; Thulasidasan, Arun Kumar T.; Vijayakurup, Vinod; Shah, Shabna; Anwer, Shabna; Joseph, Sophia M.; Antony, Jayesh; Veena, Kollery Suresh; Sundaram, Sankar; Marelli, Udaya K.; Lankalapalli, Ravi S.; Anto, Ruby John

    2016-01-01

    We report, for the first time, the remarkable efficacy of uttroside B, a potent saponin from Solanum nigrum Linn, against liver cancer. The compound has been isolated and characterized from the leaves of Solanum nigrum Linn, a plant widely used in traditional medicine and is a rich resource of several anticancer molecules. Uttroside B, that comprises of β-D-glucopyranosyl unit at C-26 of the furostanol and β-lycotetraosyl unit at C-3, is ten times more cytotoxic to the liver cancer cell line, HepG2 (IC50: 0.5 μM) than sorafenib (IC50: 5.8 μM), the only FDA-approved drug for liver cancer. Moreover, it induces cytotoxicity in all liver cancer cell lines, irrespective of their HBV status, while being non-toxic to normal immortalized hepatocytes. It induces apoptosis in HepG2 cells by down-regulating mainly the activation of MAPK and mTOR pathways. The drastic reduction in HepG2-xenograft tumor size achieved by uttroside B in NOD-SCID mice and substantiation of its biological safety through both acute and chronic toxicity studies in Swiss albino mice warrants clinical validation of the molecule against hepatic cancer, for which, the chemotherapeutic armamentarium currently has limited weapons. PMID:27808117

  7. Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo.

    PubMed

    Chen, Zhen; Chen, Yifan; Xu, Meng; Chen, Likun; Zhang, Xu; To, Kenneth Kin Wah; Zhao, Hongyun; Wang, Fang; Xia, Zhongjun; Chen, Xiaoqin; Fu, Liwu

    2016-08-01

    The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo Our results showed that osimertinib significantly increased the sensitivity of ABCB1- and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [(125)I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1- and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic. Mol Cancer Ther; 15(8); 1845-58. ©2016 AACR.

  8. Detrimental effects of chemotherapeutics and other drugs on the endothelium: A call for endothelial toxicity profiling.

    PubMed

    Wojcik, Tomasz; Szczesny, Ewa; Chlopicki, Stefan

    2015-08-01

    The vascular endothelium is a real "maestro of circulation", and endothelial dysfunction leads to atherothrombosis, its cardiovascular complications, as well as to many other diseases. It is surprising that quite a large number of drugs seem to hamper the vasoprotective mechanisms of the endothelium, possibly promoting the development of cardiovascular diseases in patients initially treated for non-cardiological conditions. Toxicity profiling (including cardiac and liver toxicity assessment) is a routine procedure performed during pre-clinical drug development. Unfortunately, endothelium-dependent side effects are not taken into account in standard toxicity profiling protocols, as the "endothelial safety" of drugs is not required in order to enter the clinical phase of drug development. Presumably, this might be one of the reasons why several efficient therapeutics, including rofecoxib (COX-2 inhibitor), torcetrapib (CETP-inhibitor), and bardoxolone (Nrf2 activator), have unexpectedly displayed clinically significant cardiovascular hazard, resulting in their withdrawal from the market or alarming comments, respectively. In this review, we will briefly characterize the endothelial activity profiles of chemotherapeutics, antidepressants and antipsychotics-all drugs prescribed for severe, life-threatening and/or life-long diseases-and will show that at least some of them may display clinically relevant detrimental effects on endothelial function.

  9. A tumor vessel-targeting fusion protein elicits a chemotherapeutic bystander effect in pancreatic ductal adenocarcinoma

    PubMed Central

    Chen, Chun-Te; Chen, Yi-Chun; Du, Yi; Han, Zhenbo; Ying, Haoqiang; Bouchard, Richard R; Hsu, Jennifer L; Hsu, Jung-Mao; Mitcham, Trevor M; Chen, Mei-Kuang; Sun, Hui-Lung; Chang, Shih-Shin; Li, Donghui; Chang, Ping; DePinho, Ronald A; Hung, Mien-Chie

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by a prominent desmoplastic stroma that may constrain tumor progression but also limit the access of therapeutic drugs. In this study, we explored a tumor-targeting strategy that enlists an engineered anti-angiogenic protein consisting of endostatin and cytosine deaminase linked to uracil phosphoribosyltransferase (EndoCD). This protein selectively binds to tumor vessels to compromise tumor angiogenesis and converts the non-toxic 5-fluorocytosine (5-FC) to the cytotoxic 5-fluorouracil to produce a chemotherapeutic bystander effect at the pancreatic tumor site. We found that resveratrol increased the protein stability of EndoCD through suppression of chymotrypsin-like proteinase activity and synergistically enhances EndoCD-mediated 5-FC-induced cell killing. In various PDAC mouse models, the EndoCD/5-FC/resveratrol regimen decreased intratumoral vascular density and stroma formation and enhances apoptosis in tumors cells as well as in surrounding endothelial, pancreatic stellate, and immune cells, leading to reduced tumor growth and extended survival. Thus, the EndoCD/5-FC/resveratrol combination may be an effective treatment option for PDAC.

  10. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

    PubMed

    Patil, Abhijit A; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D; Roylance, Anthony; Kriplani, Deepti H; Myers, Katie N; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A; Collis, Spencer J

    2014-08-15

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

  11. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

    PubMed Central

    Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

    2014-01-01

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

  12. Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro

    PubMed Central

    2014-01-01

    Background Given the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about possible interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during chemotherapy. In the in vitro study presented here the effect of standardized mistletoe preparations on the cytostatic and cytotoxic activity of several common conventional chemotherapeutic drugs was investigated using different cancer cell lines. Methods Human breast carcinoma cell lines HCC1937 and HCC1143 were treated with doxorubicin hydrochloride, pancreas adenocarcinoma cell line PA-TU-8902 with gemcitabine hydrochloride, prostate carcinoma cell line DU145 with docetaxel and mitoxantrone hydrochloride and lung carcinoma cell line NCI-H460 was treated with docetaxel and cisplatin. Each dose of the respective chemotherapeutic drug was combined with Viscum album extract (VAE) in clinically relevant concentrations and proliferation and apoptosis were measured. Results VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect. Conclusions Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the exposition of cancer cells to chemotherapeutic drugs and VAE simultaneously. PMID:24397864

  13. N-acetylaspartate (NAA) induces neuronal differentiation of SH-SY5Y neuroblastoma cell line and sensitizes it to chemotherapeutic agents

    PubMed Central

    Mazzoccoli, Carmela; Ruggieri, Vitalba; Tataranni, Tiziana; Agriesti, Francesca; Laurenzana, Ilaria; Fratello, Angelo; Capitanio, Nazzareno; Piccoli, Claudia

    2016-01-01

    Neuroblastoma is the most commonly extra-cranial solid tumor of childhood frequently diagnosed. The nervous system-specific metabolite N-acetylaspartate (NAA) is synthesized from aspartate and acetyl-CoA in neurons, it is among the most abundant metabolites present in the central nervous system (CNS) and appears to be involved in many CNS disorders. The functional significance of the high NAA concentration in the brain remains uncertain, but it confers to NAA a unique clinical significance exploited in magnetic resonance spectroscopy. In the current study, we show that treatment of SH-SY5Y neuroblastoma-derived cell line with sub-cytotoxic physiological concentrations of NAA inhibits cell growth. This effect is partly due to enhanced apoptosis, shown by decrease of the anti-apoptotic factors survivin and Bcl-xL, and partly to arrest of the cell-cycle progression, linked to enhanced expression of the cyclin-inhibitors p53, p21Cip1/Waf1 and p27Kip1. Moreover, NAA-treated SH-SY5Y cells exhibited morphological changes accompanied with increase of the neurogenic markers TH and MAP2 and down-regulation of the pluripotency markers OCT4 and CXCR4/CD184. Finally, NAA-pre-treated SH-SY5Y cells resulted more sensitive to the cytotoxic effect of the chemotherapeutic drugs Cisplatin and 5-fluorouracil. To our knowledge, this is the first study demonstrating the neuronal differentiating effects of NAA in neuroblastoma cells. NAA may be a potential preconditioning or adjuvant compound in chemotherapeutic treatment. PMID:27036033

  14. Differential Interactions of Cytochrome P450 3A5 and 3A4 with Chemotherapeutic Agent-Vincristine: A Comparative Molecular Dynamics Study.

    PubMed

    Saba, Nikhat; Bhuyan, Rajabrata; Nandy, Suman Kumar; Seal, Alpana

    2015-01-01

    The chemotherapeutic agent vincristine, used for treatment of acute lymphoblastic leukemia is metabolized preferentially by polymorphic cytochrome P450 3A5 (CYP3A5) with higher clearance rate than cytochrome P450 3A4 (CYP3A4). As a result, CYP3A5 expressers have a reduced amount of vincristine-induced peripheral neuropathy than non-expressers. We modeled the structure of CYP3A5 and its interaction with vincristine, compared with CYP3A4-vincristine complex using molecular docking and simulation studies. This relative study helped us to understand the molecular mechanisms behind the interaction at the atomic level through interaction energy, binding free energy, hydrogen bond and solvent accessible surface area analysis - giving an insight into the binding mode and the main residues involved in this particular interaction. Our results show that the interacting groups get closer in CYP3A5-vincristine complex due to different orientation of vincristine. This leads to higher binding affinity of vincristine towards CYP3A5 compared to CYP3A4 and explains the preferential metabolism of vincristine by CYP3A5. We believe that, the results of the current study will be helpful for future studies on structure-based drug design in this area.

  15. A Quinoxaline Derivative as a Potent Chemotherapeutic Agent, Alone or in Combination with Benznidazole, against Trypanosoma cruzi

    PubMed Central

    Rodrigues, Jean Henrique da Silva; Ueda-Nakamura, Tânia; Corrêa, Arlene Gonçalves; Sangi, Diego Pereira; Nakamura, Celso Vataru

    2014-01-01

    Background Chagas’ disease is a condition caused by the protozoan Trypanosoma cruzi that affects millions of people, mainly in Latin America where it is considered endemic. The chemotherapy for Chagas disease remains a problem; the standard treatment currently relies on a single drug, benznidazole, which unfortunately induces several side effects and it is not successful in the cure of most of the chronic patients. In order to improve the drug armamentarium against Chagas’ disease, in the present study we describe the synthesis of the compound 3-chloro-7-methoxy-2-(methylsulfonyl) quinoxaline (quinoxaline 4) and its activity, alone or in combination with benznidazole, against Trypanosoma cruzi in vitro. Methodology/Principal Findings Quinoxaline 4 was found to be strongly active against Trypanosoma cruzi Y strain and more effective against the proliferative forms. The cytotoxicity against LLCMK2 cells provided selective indices above one for all of the parasite forms. The drug induced very low hemolysis, but its anti-protozoan activity was partially inhibited when mouse blood was added in the experiment against trypomastigotes, an effect that was specifically related to blood cells. A synergistic effect between quinoxaline 4 and benznidazole was observed against epimastigotes and trypomastigotes, accompanied by an antagonistic interaction against LLCMK2 cells. Quinoxaline 4 induced several ultrastructural alterations, including formations of vesicular bodies, profiles of reticulum endoplasmic surrounding organelles and disorganization of Golgi complex. These alterations were also companied by cell volume reduction and maintenance of cell membrane integrity of treated-parasites. Conclusion/Significance Our results demonstrated that quinoxaline 4, alone or in combination with benznidazole, has promising effects against all the main forms of T. cruzi. The compound at low concentrations induced several ultrastructural alterations and led the parasite to an

  16. Therapeutic Potential and Molecular Mechanisms of Emblica officinalis Gaertn in Countering Nephrotoxicity in Rats Induced by the Chemotherapeutic Agent Cisplatin

    PubMed Central

    Malik, Salma; Suchal, Kapil; Bhatia, Jagriti; Khan, Sana I.; Vasisth, Swati; Tomar, Ameesha; Goyal, Sameer; Kumar, Rajeev; Arya, Dharamvir S.; Ojha, Shreesh K.

    2016-01-01

    Emblica officinalis Gaertn. belonging to family Euphorbiaceae is commonly known as Indian gooseberry or “Amla” in India. It is used as a ‘rejuvenating herb’ in traditional system of Indian medicine. It has been shown to possess antioxidant, anti-inflammatory and anti-apoptotic effects. Thus, on the basis of its biological effects, the present study was undertaken to evaluate the protective effect of the dried fruit extract of the E. Officinalis (EO) in cisplatin-induced nephrotoxicity in rats and also to evaluate the mechanism of its nephroprotection. The study was done on male albino Wistar rats. They were divided into six groups (n = 6) viz. control, cisplatin-control, cisplatin and EO (150, 300, and 600 mg/kg; p.o. respectively in different groups) and EO only (600 mg/kg; p.o. only). EO was administered orally to the rats for a period of 10 days and on the 7th day, a single injection of cisplatin (8 mg/kg; i.p.) was administered to the cisplatin-control and EO treatment groups. The rats were sacrificed on the 10th day. Cisplatin-control rats had deranged renal function parameters and the kidney histology confirmed the presence of acute tubular necrosis. Furthermore, there were increased oxidative stress, apoptosis and inflammation along with higher expression of MAPK pathway proteins in the rat kidney from the cisplatin-control group. Contrary to this, EO (600 mg/kg) significantly normalized renal function, bolstered antioxidant status and ameliorated histological alterations. The inflammation and apoptosis were markedly lower in comparison to cisplatin-control rats. Furthermore, EO (600 mg/kg) inhibited MAPK phosphorylation which was instrumental in preserving renal function and morphology. In conclusion, the results of our study demonstrated that EO attenuated cisplatin-induced nephrotoxicity in rats through suppression of MAPK induced inflammation and apoptosis. PMID:27752245

  17. Efficacy of dietary antioxidants combined with a chemotherapeutic agent on human colon cancer progression in a fluorescent orthotopic mouse model.

    PubMed

    Ma, Huaiyu; Das, Tapas; Pereira, Suzette; Yang, Zhijian; Zhao, Ming; Mukerji, Pradip; Hoffman, Robert M

    2009-07-01

    We report here the efficacy of dietary antioxidants in combination with chemotherapy on tumor growth in the orthotopic COLO-205-green fluorescent protein (GFP) human colon cancer mouse model. The orthotopically-transplanted nude mice used for the study were randomly divided into 5 groups (A-E) after surgical orthotopic implantation (SOI) of tumor tissue. The following diets were given: Diet A, modified AIN-93M mature rodent diet with 4% fish oil; Diet B, modified AIN-93M which contains added antioxidants vitamin A, vitamin E, and selenium at levels present in the standard AIN-93M diet; Diet C, Diet A without added antioxidants vitamin A, vitamin E, or selenium; Diet D, Diet A with 5 times the amount of added antioxidants vitamin A, vitamin E, and selenium present in Diet B. Cisplatin, 7 mg/kg, was administered intraperitoneally on day 16 after SOI. Throughout the course of treatment, noninvasive whole-body imaging, based on the GFP expression of the tumor, permitted visualization of tumor progression. At sacrifice, the mean tumor weights showed significant statistical differences in all of the treated groups compared to the negative control (no cisplatin treatment) (p effective against tumor growth in combination with cisplatin in the fluorescent mouse model of colon cancer COLO-205 GFP. The results of the present study therefore indicate enhancement of cisplatin efficacy by high-dose antioxidants in combination with fish oil for colon cancer progression and suggests the design of clinical trials for this regimen.

  18. Apoptosis-like cell death pathways in the unicellular parasite Toxoplasma gondii following treatment with apoptosis inducers and chemotherapeutic agents: a proof-of-concept study.

    PubMed

    Ni Nyoman, Ayu Dewi; Lüder, Carsten G K

    2013-06-01

    Ancient pathways of an apoptosis-like cell death have been identified in unicellular eukaryotes including protozoan parasites. Here, we examined programmed cell death in the apicomplexan Toxoplasma gondii which is a common intracellular pathogen of humans and warm-blooded animals. Treatment of extracellular T. gondii with various pro-apoptotic stimuli significantly induced DNA strand breaks as revealed by TUNEL and flow cytometry. Using staurosporine or miltefosine as pro-apoptotic stimuli, parasites also presented a reduced cell size, i.e. pyknosis and externalized phosphatidylserine while the plasma membrane remained intact. Importantly, staurosporine also induced DNA strand breaks in intracellular T. gondii. Data mining of the Toxoplasma genome resource identified 17 putative cell death-associated genes encoding proteases, a nuclease and several apoptosis regulators. Staurosporine-treated parasites but not controls strongly up-regulated several of these genes in a time-dependent fashion with a putative PDCD2 protein being more than 100-fold up-regulated. However, the mitochondrial membrane potential (ΔΨ(m)) remained intact and caspase-like activity increased only slightly during staurosporine-triggered cell death. As compared to staurosporine, the transcriptional response of parasites to miltefosine was more restricted but PDCD2 was again strongly induced. Furthermore, T. gondii lost their ΔΨ(m) and rapidly presented strong caspase-like activity during miltefosine treatment. Consequently, protease inhibitors abrogated miltefosine-induced but not staurosporine-induced Toxoplasma cell death. Finally, toxoplasmacidal drugs triggered DNA strand breaks in extracellular T. gondii. Interestingly, clindamycin also induced markers of an apoptosis-like cell death in intracellular parasites. Together, the data indicate that T. gondii possesses ancient apoptosis-like cell death machinery which can be triggered by chemotherapeutic agents.

  19. Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells.

    PubMed

    Yi, Yong Weon; Kang, Hyo Jin; Kim, Hee Jeong; Hwang, Jae Seok; Wang, Antai; Bae, Insoo

    2013-09-01

    Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers.

  20. Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery

    PubMed Central

    Fang, Yi-Ping; Wu, Pao-Chu; Huang, Yaw-Bin; Tzeng, Cherng-Chyi; Chen, Yeh-Long; Hung, Yu-Han; Tsai, Ming-Jun; Tsai, Yi-Hung

    2012-01-01

    Background The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenyl) amino]furo[2,3-b]quinoline (PK-L4) is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection. Aims To utilize solid lipid nanoparticles (SLNs) modified with polyethylene glycol (PEG) to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration. Results The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE%) of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%–64% in the human lung carcinoma cell line (A549), 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7), and 95% in the human breast adenocarcinoma cell line (MDA-MB-231). The amount of PK-L4 released by SLNs with PEG was significantly higher than that from the PK-L4 solution (P < 0.05). After intravenous bolus of the PK-L4-loaded SLNs with PEG, there was a marked significant difference in half-life alpha (0.136 ± 0.046 hours) when compared with the PK-L4 solution (0.078 ± 0.023 hours); also the area under the curve from zero to infinity did not change in plasma when compared to the PK-L4 solution. This demonstrated that PK-L4-loaded SLNs were rapidly distributed from central areas to tissues and exhibited higher accumulation in specific organs. The highest deposition of PK-L4-loaded SLNs

  1. Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models.

    PubMed

    Perera, Yasser; Toro, Neylen Del; Gorovaya, Larisa; Fernandez-DE-Cossio, Jorge; Farina, Hernan G; Perea, Silvio E

    2014-11-01

    CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives.

  2. Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

    PubMed Central

    PERERA, YASSER; TORO, NEYLEN DEL; GOROVAYA, LARISA; FERNANDEZ-DE-COSSIO, JORGE; FARINA, HERNAN G.; PEREA, SILVIO E.

    2014-01-01

    CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives. PMID:25279177

  3. Stable transfection of extrinsic Smac gene enhances apoptosis-inducing effects of chemotherapeutic drugs on gastric cancer cells

    PubMed Central

    Zheng, Li-Duan; Tong, Qiang-Song; Wang, Liang; Liu, Jun; Qian, Wei

    2005-01-01

    AIM: To explore the feasibility of enhancing apoptosis-inducing effects of chemotherapeutic drugs on human gastric cancer cells by stable transfection of extrinsic Smac gene. METHODS: After Smac gene was transferred into gastric cancer cell line MKN-45, subclone cells were obtained by persistent G418 selection. Cellular Smac gene expression was determined by RT-PCR and Western blotting. After treatment with mitomycin (MMC) as an apoptotic inducer, in vitro cell growth activities were investigated by trypan blue-staining method and MTT colorimetry. Cell apoptosis and its rates were determined by electronic microscopy, annexin V-FITC and propidium iodide staining flow cytometry. Cellular caspase-3 protein expression and its activities were assayed by Western blotting and colorimetry. RESULTS: When compared with MKN-45 cells, the selected subclone cell line MKN-45/Smac had significantly higher Smac mRNA (3.12±0.21 vs 0.82±0.14, t = 7.52, P<0.01) and protein levels (4.02±0.24 vs 0.98±0.11, t = 8.32, P<0.01). After treatment with 10 μg/mL MMC for 6-24 h, growth inhibition rate of MKN-45/Smac (15.8±1.2-54.8±2.9%) was significantly higher than that of MKN-45 (5.8±0.4- 24.0±1.5%, t = 6.42, P<0.01). Partial MKN-45/Smac cancer cells presented characteristic morphological changes of apoptosis under the electronic microscope with an apoptosis rate of 36.4±2.1%, which was significantly higher than that of MKN-45 (15.2±0.8%, t = 9.25, P<0.01). Compared with MKN-45, caspase-3 expression levels in MKN-45/Smac were improved significantly (3.39±0.42 vs 0.96±0.14, t = 8.63, P<0.01), while its activities were 3.25 times as many as those of MKN-45 (0.364±0.010 vs 0.112±0.007, t = 6.34, P<0.01). CONCLUSION: Stable transfection of extrinsic Smac gene and its over-expression in gastric cancer cell line can significantly enhance cellular caspase-3 expression and activities, ameliorate apoptosis-inducing effects of mitomycin C on cancer cells, which is a novel strategy to

  4. Effects of St. John’s Wort and Vitamin E on Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2003-05-01

    pharmacokinetics of doxorubicin related to dietary intake of vitamin E or St . John’s wort . Rats ingesting St . John’s wort had similar survival at each...doxorubicin. Our studies indicate that vitamin E and St . John’s wort neither increase nor protect against the toxicity of doxorubicin or docetaxel in rats.

  5. Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model.

    PubMed

    Dickey, Jennifer S; Gonzalez, Yanira; Aryal, Baikuntha; Mog, Steven; Nakamura, Asako J; Redon, Christophe E; Baxa, Ulrich; Rosen, Elliot; Cheng, Gang; Zielonka, Jacek; Parekh, Palak; Mason, Karen P; Joseph, Joy; Kalyanaraman, Balaraman; Bonner, William; Herman, Eugene; Shacter, Emily; Rao, V Ashutosh

    2013-01-01

    Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-α) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of

  6. Efficacy of combined photothermal therapy and chemotherapeutic drugs

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Shih, En-Chung; Hirschberg, Henry

    2015-03-01

    Hyperthermia has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of a number of commonly used chemotherapeutic drugs (bleomycin, doxorubicin and cisplatin) with photothermal therapy (PTT)-induced hyperthermia in an in vitro system consisting of human head and neck squamous carcinoma cells and murine lymphocytic monocytes which were used as delivery vehicles for gold-silica nanoshells (AuNS). PTT was accomplished via near infra-red (NIR) irradiation of AuNS. The results showed that PTT combined with cisplatin resulted in only a mild degree of synergism while additive effects were observed for concurrent treatments of PTT and doxorubicin and PTT and bleomycin.

  7. [Effects of cucurmosin combined with common chemotherapeutics on proliferation and apoptosis of NB4 cells].

    PubMed

    Xle, Jie-Ming; Liu, Mei; Liu, Ting-Bo; Chen, Ming-Huang; Yang, Ai-Qin; Yang, Pei

    2012-12-01

    This study was aimed to investigate the proliferation inhibition and apoptosis induction of cucurmosin (CUS) combined with all trans-retinoic acid (ATRA) or arsenic trioxide (ATO) on human acute promyelocytic leukemia cell line NB4. MTT method was used to determine the proliferative inhibition of CUS combined with ATRA or ATO on NB4 cells, and flow cytometry was used to determine the apoptosis induction effect of CUS combined with ATRA or ATO on NB4 cells. Jin's formula was used to assess the synergistic effect of this combinations. The results showed that, compared with single drug, the proliferation inhibitory ratio and apoptotic ratio of CUS combined with ATRA or ATO on NB4 cells was higher than CUS, ATRA and ATO alone. The synergistic index (q) were all larger than 0.85, and the combined effects were significant at low concentrations. It is concluded that the CUS combined with ATRA or ATO synergistically increases the effects of proliferative inhibition and apoptosis induction on NB4 cells.

  8. The effects of humanin and its analogues on male germ cell apoptosis induced by chemotherapeutic drugs.

    PubMed

    Jia, Yue; Ohanyan, Aikoui; Lue, Yan-He; Swerdloff, Ronald S; Liu, Peter Y; Cohen, Pinchas; Wang, Christina

    2015-04-01

    Human (HN) prevents stress-induced apoptosis in many cells/tissues. In this study we showed that HN ameliorated chemotherapy [cyclophosphamide (CP) and Doxorubicin (DOX)]-induced male germ cell apoptosis both ex vivo in seminiferous tubule cultures and in vivo in the testis. HN acts by several putative mechanisms via binding to: an IL-12 like trimeric membrane receptor; BAX; or insulin-like growth factor binding protein-3 (IGFBP-3, a proapoptotic factor). To understand the mechanisms of HN on male germ cell apoptosis, we studied five HN analogues including: HNG (HN-S14G, a potent agonist), HNG-F6A (no binding to IGFBP-3), HN-S7A (no self-dimerization), HN-C8P (no binding to BAX), and HN-L12A (a HN antagonist) on CP-induced male germ cell apoptosis in mice. CP-induced germ cell apoptosis was inhibited by HN, HNG, HNG-F6A, HN-S7A, and HN-C8P (less effective); but not by HN-L12A. HN-L12A, but not HN-S7A or HN-C8P, blocked the protective effect of HN against CP-induced male germ cell apoptosis. HN, HN-S7A, and HN-C8P restored CP-suppressed STAT3 phosphorylation. These results suggest that HN: (1) decreases DOX (ex vivo) and CP (in vivo) induced male germ cell apoptosis; (2) action is mediated by the membrane receptor/STAT3 with minor contribution by BAX-binding pathway; (3) self-dimerization or binding to IGFBP-3 may not be involved in HN's effect in testis. HN is an important molecule in the regulation of germ cell homeostasis after injury and agonistic analogues may be developed for treating male infertility or protection against chemotherapy side effects.

  9. The Effects of Humanin and Its Analogues on Male Germ Cell Apoptosis Induced by Chemotherapeutic Drugs

    PubMed Central

    Jia, Yue; Ohanyan, Aikoui; Lue, Yan-He; Swerdloff, Ronald S.; Liu, Peter Y.; Cohen, Pinchas; Wang, Christina

    2015-01-01

    Human (HN) prevents stress-induced apoptosis in many cells/tissues. In this study we showed that HN ameliorated chemotherapy (Cyclophosphamide, CP and Doxorubicin, DOX)-induced male germ cell apoptosis both ex vivo in seminiferous tubule cultures and in vivo in the testis. HN acts by several putative mechanisms via binding to: an IL-12 like trimeric membrane receptor; BAX; or Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3, a proapoptotic factor). To understand the mechanisms of HN on male germ cell apoptosis, we studied five HN analogues including: HNG (HN-S14G, a potent agonist), HNG-F6A (no binding to IGFBP-3), HN-S7A (no self-dimerization), HN-C8P (no binding to BAX), and HN-L12A (a HN antagonist) on CP-induced male germ cell apoptosis in mice. CP-induced germ cell apoptosis was inhibited by HN, HNG, HNG-F6A, HN-S7A, and HN-C8P (less effective); but not by HN-L12A. HN-L12A, but not HN-S7A or HN-C8P, blocked the protective effect of HN against CP-induced male germ cell apoptosis. HN, HN-S7A, and HN-C8P restored CP-suppressed STAT3 phosphorylation. These results suggest that HN: 1) decreases DOX (ex vivo) and CP (in vivo) induced male germ cell apoptosis; 2) action is mediated by the membrane receptor/STAT3 with minor contribution by BAX-binding pathway; 3) self-dimerization or binding to IGFBP-3 may not be involved in HN’s effect in testis. HN is an important molecule in the regulation of germ cell homeostasis after injury and agonistic analogues may be developed for treating male infertility or protection against chemotherapy side effects. PMID:25666707

  10. Proteomic analysis of blood cells in fish exposed to chemotherapeutics: evidence for long term effects.

    PubMed

    Pierrard, Marie-Aline; Kestemont, Patrick; Phuong, Nguyen Thanh; Tran, Minh Phu; Delaive, Edouard; Thezenas, Marie-Laëtitia; Dieu, Marc; Raes, Martine; Silvestre, Frédéric

    2012-04-18

    Proteomics technology are increasingly used in ecotoxicological studies to characterize and monitor biomarkers of exposure. The present study aims at identifying long term effects of malachite green (MG) exposure on the proteome of peripheral blood mononuclear cells (PBMC) from the Asian catfish, Pangasianodon hypophthalmus. A common (0.1 ppm) concentration for therapeutic treatment was applied twice with a 72 h interval. PBMC were collected directly at the end of the second bath of MG (T1) and after 1 month of decontamination (T2). Analytical 2D-DIGE gels were run and a total of 2551±364 spots were matched. Among them, MG induced significant changes in abundance of 116 spots with no recovery after one month of decontamination. Using LC-MS/MS and considering single identification per spot, we could identify 25 different proteins. Additionally, MG residues were measured in muscle and in blood indicating that leuco-MG has almost totally disappeared after one month of decontamination. This work highlights long term effects of MG treatment on the PBMC proteome from fish intended for human consumption.

  11. Chemotherapeutic (cyclophosphamide) effects on rat breast tumor hemodynamics monitored by multi-channel NIRS

    NASA Astrophysics Data System (ADS)

    Kim, Jae G.; Zhao, Dawen; Mason, Ralph P.; Liu, Hanli

    2005-04-01

    We previously suggested that the two time constants quantified from the increase of tumor oxyhemoglobin concentration, ▵ [HbO2], during hyperoxic gas intervention are associated with two blood flow/perfusion rates in well perfused and poorly perfused regions of tumors. In this study, our hypothesis is that when cancer therapy is applied to a tumor, changes in blood perfusion will occur and be detected by the NIRS. For experiments, systemic chemotherapy, cyclophosphamide (CTX), was applied to two groups of rats bearing syngeneic 13762NF mammary adenocarcinomas: one group received a single high dose i. p. (200 mg/kg CTX) and the other group continuous low doses (20 mg/kg CTX i. p. for 10 days). Time courses of changes in tumor ▵ [HbO2] were measured at four different locations on the breast tumors non-invasively with an inhaled gas sequence of air-oxygen-air before and after CTX administration. Both rat body weight and tumor volume decreased after administration of high dose CTX, but continuous low doses showed decrease of tumor volume only. Baselines (without any therapy) intra- and inter-tumor heterogeneity of vascular oxygenation during oxygen inhalation were similar to our previous observations. After CTX treatment, significant changes in vascular hemodynamic response to oxygen inhalation were observed from both groups. By fitting the increase of ▵ [HbO2] during oxygen inhalation, we have obtained changes of vascular structure ratio and also of perfusion rate ratio before and after chemotherapy. The preliminary results suggest that cyclophosphamide has greatest effect on the well perfused tumor vasculature. Overall, our study supports our earlier hypothesis, proving that the effects of chemotherapy in tumor may be monitored non-invasively by using NIRS to detect changes of hemodynamics induced with respiratory challenges.

  12. Molecular effects of chemotherapeutic drugs and their modulation by antioxidants in the testis.

    PubMed

    Narayana, Kilarkaje; Al-Bader, Maie; Mousa, Alyaa; Khan, Khalid M

    2012-01-15

    Cisplatin-based chemotherapy regimens are preferred in the treatment of a variety of cancers. The present study investigated early cumulative molecular effects of therapeutic dose-levels of bleomycin, etoposide and cisplatin (BEP) in the testis and their modulation by an antioxidant cocktail (AO). Adult male Sprague-Dawley rats (N=7/group [G]) were treated with BEP as follows: G1 - control; G2 - AO (α-tocopherol [100 mg/kg], l-ascorbic acid [50 mg/kg], Zn [40 mg/l] and Se [100 μg/l]); G3 - B, 1.5 mg/kg on day 2; E, 15 mg/kg and P, 3 mg/kg for 4 days, and G4 - similar to G3 but also treated with AO for 4 days. In G3, the testis weight, sperm count and motility, and activities of enzymatic antioxidants decreased and lipid peroxidation increased compared to that in G1 (P<0.05). Seminiferous epithelial sloughing and degeneration were observed. In G3, mRNA levels of p53, Bcl-2 and Bax were unaltered but protein expression of p53 and Bax was up-regulated and that of Bcl-2 was down-regulated (P<0.05). These changes led to an increase in terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) positive germ cells indicating cell death (P<0.05). The AO recovered the BEP-induced molecular alterations to control levels. The mechanism of BEP-induced early testicular damage involves the initiation of oxidative stress, up-regulation of pro-apoptotic proteins and induction of cell death. Further, the induced testicular structural changes are negligible and less than those observed in single drug exposure studies reported in literature. The AO significantly ameliorates the BEP-induced pathogenesis of testicular damage suggesting its potential therapeutic uses.

  13. Potentiation of chemotherapeutics by bromelain and N-acetylcysteine: sequential and combination therapy of gastrointestinal cancer cells

    PubMed Central

    Amini, Afshin; Masoumi-Moghaddam, Samar; Ehteda, Anahid; Liauw, Winston; Morris, David Lawson

    2016-01-01

    Intraperitoneal chemotherapy together with cytoreductive surgery is the standard of care for a number of peritoneal surface malignancies. However, this approach fails to maintain the complete response and disease recurs due to microscopic residual disease. Although safer than systemic chemotherapy regimens, locoregional treatment with chemotherapeutics can induce toxicity which is a major concern affecting the patient’s treatment protocol and outcome. For an enhanced treatment efficacy, efforts should be made to maximize cytotoxic effects of chemotherapeutic agents on tumor cells while minimizing their toxic effects on host cells. Bromelain and N-acetylcysteine are two natural agents with good safety profiles shown to have anti-cancer effects. However, their interaction with chemotherapeutics is unknown. In this study, we investigated if these agents have the potential to sensitize in vitro gastrointestinal cancer models to cisplatin, paclitaxel, 5-fluorouracil, and vincristine. The drug-drug interaction was also analyzed. Our findings suggest that combination of bromelain and N-acetylcysteine with chemotherapeutic agents could give rise to an improved chemotherapeutic index in therapeutic approaches to peritoneal surface malignancies of gastrointestinal origin so that maximum benefits could result from less toxic and more patient-friendly doses. This represents a potentially efficacious strategy for the enhancement of microscopic cytoreduction and is a promising area for future research. PMID:27186409

  14. In vitro DNA binding profile of enantiomeric dinuclear Cu(II)/Ni(II) complexes derived from l-/d-histidine-terepthaldehyde reduced Schiff base as potential chemotherapeutic agents.

    PubMed

    Yousuf, Imtiyaz; Arjmand, Farukh

    2016-11-01

    New chiral reduced Schiff base ligands, L1 and L2 derived from l-/d-histidine and terepthaldehyde, and their Cu(II) and Ni(II) dinuclear complexes 1 &2 (a and b) were synthesized and thoroughly characterized by various spectroscopic techniques. Comparative binding profile of both l-/d-enantiomeric Cu(II) and Ni(II) complexes with ct-DNA was studied by employing optical and spectroscopic techniques to evaluate their enantiopreferential selectivity towards molecular target DNA and thereby explore their relative chemotherapeutic potential. Quantitative assessment of DNA binding propensity was ascertained by calculating Kb, K and Ksv values of 1 &2 (a and b) which demonstrated higher binding affinity of l-enantiomeric Cu(II) complex, 1a and followed the order as 1a>1b>2a>2b. Scanning electron microscopy (SEM) was used to analyze the morphological changes of the DNA condensate in presence of complexes 1 (a and b). The SEM micrographs condensates revealed morphological transitions and formation of different structural features implicating the condensation process between the complexes and biomolecule occurred to form compact massive structures. The gel electrophoretic assay of complex 1a was carried out with pBR322 plasmid DNA which revealed an efficient cleaving ability of the complex via oxidative pathway with the involvement of singlet oxygen ((1)O2) and the superoxide anion (O2(•-)) radicals as the ROS responsible the cleavage reactions. Molecular docking studies of 1 (a and b) with DNA revealed selective recognition of G-C residues of the narrow minor groove of the DNA duplex and complex 1a demonstrated binding affinity towards DNA ascertained from its higher binding energy values. Furthermore, the cytotoxic assessment of 1a was examined on a panel of cancer cell lines of different histological origin employing SRB assay which revealed remarkably good cytotoxic activity towards HL60, HeLa and MCF7 cancer cell lines.

  15. Enhancing the Efficacy of Chemotherapeutic Breast Cancer Treatment with Nonanticoagulant Heparins

    DTIC Science & Technology

    2008-05-01

    intervals throughout the course of treatment. LMWH compounds (Enoxaparin or non- anticoagulant heparin NACH) given together with chemotherapeutic agent ... Anticoagulants , Antiplatelets , and Thrombolytics. 2004. SA Mousa (Ed). Humana Press Inc., 133-155, 2004. 11. Mousa SA, Mohamed S. Anti-angiogenic mechanisms...doxorubicin decreased tumor growth rate and prolong survival in animals bearing MCF7 wild-type tumors. These agents appeared to be less effective in

  16. Double-Walled Microparticles-Embedded Self-Cross-Linked, Injectable, and Antibacterial Hydrogel for Controlled and Sustained Release of Chemotherapeutic Agents.

    PubMed

    Davoodi, Pooya; Ng, Wei Cheng; Yan, Wei Cheng; Srinivasan, Madapusi P; Wang, Chi-Hwa

    2016-09-07

    First-line cancer chemotherapy has been prescribed for patients suffered from cancers for many years. However, conventional chemotherapy provides a high parenteral dosage of anticancer drugs over a short period, which may cause serious toxicities and detrimental side effects in healthy tissues. This study aims to develop a new drug delivery system (DDS) composed of double-walled microparticles and an injectable hydrogel for localized dual-agent drug delivery to tumors. The uniform double-walled microparticles loaded with cisplatin (Cis-DDP) and paclitaxel (PTX) were fabricated via coaxial electrohydrodynamic atomization (CEHDA) technique and subsequently were embedded into injectable alginate-branched polyethylenimine. The findings show the uniqueness of CEHDA technique for simply swapping the place of drugs to achieve a parallel or a sequential release profile. This study also presents the simulation of CEHDA technique using computational fluid dynamics (CFD) that will help in the optimization of CEHDA's operating conditions prior to large-scale production of microparticles. The new synthetic hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection after debulking surgery and preventing surgical site infection due to its inherent antibacterial properties. Three-dimensional MDA-MB-231 (breast cancer) spheroid studies demonstrate a superior efficacy and a greater reduction in spheroid growth for drugs released from the proposed composite formulation over a prolonged period, as compared with free drug treatment. Overall, the new core-shell microparticles embedded into injectable hydrogel can serve as a flexible controlled release platform for modulating the release profiles of anticancer drugs and subsequently providing a superior anticancer response.

  17. The chemotherapeutic effect of essential oil of Plectranthus amboinicus (Lour) on lung metastasis developed by B16F-10 cell line in C57BL/6 mice.

    PubMed

    Manjamalai, A; Grace, V M Berlin

    2013-01-01

    Current investigation is to evaluate the anticancer activity of the essential oil of Plectranthus amboinicus (Lour) on B16F-10 melanoma cell line injected C57BL/6 mice, and it was simultaneously treated with the essential oil of P. amboinicus (Lour) (50 μg/dose) via i.p. for 21 days. The present investigation exhibited the potent chemotherapeutic/chemopreventive effect of the essential oil of P. amboinicus (Lour) over lung metastasis that developed. To our knowledge, this is the first report in evaluating the effect of essential oil of P. amboinicus (Lour) using lung cancer model.

  18. Effects of Chemotherapy on the Brain in Women With Newly Diagnosed Early-Stage Breast Cancer

    ClinicalTrials.gov

    2016-05-12

    Breast Cancer; Chemotherapeutic Agent Toxicity; Cognitive/Functional Effects; Fatigue; Long-term Effects Secondary to Cancer Therapy in Adults; Neurotoxicity; Psychosocial Effects of Cancer and Its Treatment

  19. Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer.

    PubMed

    Ikeda, Hirokuni; Taira, Naruto; Nogami, Tomohiro; Shien, Kazuhiko; Okada, Masanori; Shien, Tadahiko; Doihara, Hiroyoshi; Miyoshi, Shinichiro

    2011-11-01

    Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo.

  20. Synthesis and biological activity of NOSH-naproxen (AVT-219) and NOSH-sulindac (AVT-18A) as potent anti-inflammatory agents with chemotherapeutic potential

    PubMed Central

    Kodela, Ravinder; Chattopadhyay, Mitali; Kashfi, Khosrow

    2013-01-01

    Nitric oxide- (NO) and hydrogen sulfide- (H2S) releasing naproxen (NOSH-naproxen) and NO and H2S-releasing sulindac (NOSH-sulindac) were synthesized and their cell growth inhibitory properties were evaluated in four different human cancer cell lines. These cell lines are of adenomatous (colon, pancreas), epithelial (breast), and lymphocytic (leukemia) origin. Using HT-29 human colon cancer cells, NOSH-naproxen and NOSH-sulindac increased apoptosis, and inhibited proliferation. NOSH-naproxen caused a G0/G1 whereas NOSH-sulindac caused a G2/M block in the cell cycle. Both compounds exhibited significant anti-inflammatory properties, using the carrageenan rat paw edema model. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-naproxen was approximately 8000-fold more potent than the sum of its parts in inhibiting cell growth. Our data suggest that these compounds merit further investigation as potential anti-cancer agents. PMID:24273639

  1. Experimental FT-IR, Laser-Raman and DFT spectroscopic analysis of a potential chemotherapeutic agent 6-(2-methylpropyl)-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile.

    PubMed

    Sert, Yusuf; Al-Turkistani, Abdulghafoor A; Al-Deeb, Omar A; El-Emam, Ali A; Ucun, Fatih; Çırak, Çağrı

    2014-01-01

    In this study, the experimental and theoretical vibrational frequencies of a newly synthesized potential chemotherapeutic agent namely, 6-(2-methylpropyl)-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile have been investigated. The experimental FT-IR (4000-400 cm(-1)) and Laser-Raman spectra (4000-100 cm(-1)) of the molecule in solid phase have been recorded. The theoretical vibrational frequencies and optimized geometric parameters (bond lengths and bond angles) have been calculated by using density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr) and M06-2X (the highly parametrized, empirical exchange correlation function) quantum chemical methods with 6-311++G(d,p) basis set by Gaussian 09 W software, for the first time. The assignments of the vibrational frequencies have been done by potential energy distribution (PED) analysis by using VEDA 4 software. The theoretical optimized geometric parameters and vibrational frequencies have been found to be in good agreement with the corresponding experimental data, and with the results in the literature. In addition, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies and the other related molecular energy values have been calculated and depicted.

  2. Spectroscopic detection of chemotherapeutics and antioxidants

    NASA Astrophysics Data System (ADS)

    Latka, Ines; Grüner, Roman; Matthäus, Christian; Dietzek, Benjamin; Werncke, W.; Lademann, Jürgen; Popp, Jürgen

    2012-06-01

    The hand-foot-syndrome presents a severe dermal side-effect of chemotherapeutic cancer treatment. The cause of this side-effect is the elimination of systemically administered chemotherapeutics with the sweat. Transported to the skin surface, the drugs subsequently penetrate into the skin in the manner of topically applied substances. Upon accumulation of the chemotherapeutics in the skin the drugs destroy cells and tissue - in the same way as they are supposed to act in cancer cells. Aiming at the development of strategies to illuminate the molecular mechanism underlying the handfoot- syndrome (and, in a second step, strategies to prevent this severe side-effect), it might be important to evaluate the concentration and distribution of chemotherapeutics and antioxidants in the human skin. The latter can be estimated by the carotenoid concentration, as carotenoids serve as marker substances for the dermal antioxidative status.Following the objectives outlined above, this contribution presents a spectroscopic study aiming at the detection and quantification of carotenoids and selected chemotherapeutics in human skin. To this end, spontaneous Raman scattering and coherent anti-Stokes Raman scattering (CARS) microspectroscopy are combined with two-photon excited fluorescence. While the latter technique is Please verify that (1) all pages are present, (2) all figures are correct, (3) all fonts and special characters are correct, and (4) all text and figures fit within the red margin lines shown on this review document. Complete formatting information is available at http://SPIE.org/manuscripts Return to your MySPIE To Do List at http://myspie.org and approve or disapprove this submission. Your manuscript will not be published without this approval.restricted to the detection of fluorescent chemotherapeutics, e.g., doxorubicin, the vibrational spectroscopic techniques can - in principle - be applied to any type of analyte molecules. Furthermore, we will present the

  3. Well-Defined Poly(Ortho Ester Amides) for Potential Drug Carriers: Probing the Effect of Extra- and Intracellular Drug Release on Chemotherapeutic Efficacy.

    PubMed

    Yan, Guoqing; Wang, Jun; Qin, Jiejie; Hu, Liefeng; Zhang, Panpan; Wang, Xin; Tang, Rupei

    2017-03-29

    To compare the chemotherapeutic efficacy determined by extra- and intracellular drug release strategies, poly(ortho ester amide)-based drug carriers (POEAd-C) with well-defined main-chain lengths, are successfully constructed by a facile method. POEAd-C3-doxorubicin (DOX) can be rapidly dissolved to release drug at tumoral extracellular pH (6.5-7.2), while POEAd-C6-DOX can rapidly release drug following gradual swelling at intracellular pH (5.0-6.0). In vitro cytotoxicity shows that POEAd-C3-DOX exhibits more toxic effect on tumor cells than POEAd-C6-DOX at extracellular pH, but POEAd-C6-DOX has stronger tumor penetration and inhibition in vitro and in vivo tumor models. So, POEAd-C6-DOX with the intracellular drug release strategy has stronger overall chemotherapeutic efficacy than POEAd-C3-DOX with extracellular drug release strategy. It is envisioned that these poly(ortho ester amides) can have great potential as drug carriers for efficient chemotherapy with further optimization.

  4. Mitochondria and redox homoeostasis as chemotherapeutic targets.

    PubMed

    Briehl, Margaret M; Tome, Margaret E; Wilkinson, Sarah T; Jaramillo, Melba C; Lee, Kristy

    2014-08-01

    Characteristics of cancer cells include a more oxidized redox environment, metabolic reprogramming and apoptosis resistance. Our studies with a lymphoma model have explored connections between the cellular redox environment and cancer cell phenotypes. Alterations seen in lymphoma cells made resistant to oxidative stress include: a more oxidized redox environment despite increased expression of antioxidant enzymes, enhanced net tumour growth, metabolic changes involving the mitochondria and resistance to the mitochondrial pathway to apoptosis. Of particular importance, the cells show cross-resistance to multiple chemotherapeutic agents used to treat aggressive lymphomas. Analyses of clinical and tumour data reveal the worst prognosis when patients' lymphomas have gene expression patterns consistent with the most oxidized redox environment. Lymphomas from patients with the worst survival outcomes express increased levels of proteins involved in oxidative phosphorylation, including cytochrome c. This is consistent with these cells functioning as metabolic opportunists. Using lymphoma cell models and primary lymphoma cultures, we observed enhanced killing using genetic and drug approaches which further oxidize the cellular redox environment. These approaches include increased expression of SOD2 (superoxide dismutase 2), treatment with a manganoporphyrin that oxidizes the glutathione redox couple, or treatment with a copper chelator that inhibits SOD1 and leads to peroxynitrite-dependent cell death. The latter approach effectively kills lymphoma cells that overexpress the anti-apoptotic protein Bcl-2. Given the central role of mitochondria in redox homoeostasis, metabolism and the intrinsic pathway to apoptosis, our studies support the development of new anti-cancer drugs to target this organelle.

  5. Human toxoplasmosis-Searching for novel chemotherapeutics.

    PubMed

    Antczak, Magdalena; Dzitko, Katarzyna; Długońska, Henryka

    2016-08-01

    The protozoan Toxoplasma gondii, an obligate intracellular parasite, is an etiological agent of human and animal toxoplasmosis. Treatment regimens for T. gondii-infected patients have not essentially changed for years. The most common chemotherapeutics used in the therapy of symptomatic toxoplasmosis are a combination of pyrimethamine and sulfadiazine plus folinic acid or a combination of pyrimethamine with lincosamide or macrolide antibiotics. To protect a fetus from parasite transplacental transmission, therapy of pregnant women is usually based on spiramycin, which is quite safe for the organism, but not efficient in the treatment of infected children. Application of recommended drugs limits replication of T. gondii, however, it may be associated with numerous an severe adverse effects. Moreover, medicines have no impact on the tissue cysts of the parasite located predominantly in a brain and muscles. Thus, there is urgent need to develop new drugs and establish "gold standard" treatment. In this review classical treatment of toxoplasmosis as well as potential compounds active against T. gondii have been discussed. For two last decades studies on the development of new anti-T. gondii medications have been focused on both natural and novel synthetic compounds based on existing chemical scaffolds. They have revealed several promising drug candidates characterized by a high selectivity, the low IC50 (the half maximal inhibitory concentration) and low cytotoxicity towards host cells. These drugs are expected to replace or supplement current anti-T. gondii drug arsenal soon.

  6. (Coordinated research of chemotherapeutic agents and radiopharmaceuticals)

    SciTech Connect

    Srivastava, P.C.

    1991-01-14

    The traveler received a United Nations Development Program (UNDP) Award for Distinguished Scientists to visit Indian Research Institutions including Central Drug Research Institute (CDRI), Lucknow, the host institution, in cooperation with the Council of Scientific and Industrial Research (CSIR) of India. At CDRI, the traveler had meetings to discuss progress and future directions of on-going collaborative research work on nucleosides and had the opportunity to initiate new projects with the divisions of pharmacology, biopolymers, and membrane biology. As a part of this program, the traveler also visited Sanjay Gandhi Post Graduate Institute (SGPI) of Medical Sciences, Lucknow; Board of Radiation and Isotope Technology (BRIT) and Bhabha Atomic Research Center (BARC), Bombay; Variable Energy Cyclotron Center (VECC) and Indian Institute of Chemical Biology, Calcutta. He also attended the Indo-American Society of Nuclear Medicine Meeting held in Calcutta. The traveler delivered five seminars describing various aspects of radiopharmaceutical development at the Oak Ridge National Laboratory (ORNL) and discussed the opportunities for exchange visits to ORNL by Indian scientists.

  7. The effect of chemotherapy on programmed cell death 1/programmed cell death 1 ligand axis: some chemotherapeutical drugs may finally work through immune response

    PubMed Central

    Luo, Min; Fu, Liwu

    2016-01-01

    Most tumors are immunogenic which would trigger some immune response. Chemotherapy also has immune potentiating mechanisms of action. But it is unknown whether the immune response is associated with the efficacy of chemotherapy and the development of chemoresistance. Recently, there is a growing interest in immunotherapy, among which the co-inhibitory molecules, programmed cell death 1/programmed cell death 1 ligand (PD-1/PD-L1) leads to immune evasion. Since some reports showed that conventional chemotherapeutics can induce the expression of PD-L1, we try to summarize the effect of chemotherapy on PD-1/PD-L1 axis and some potential molecules relevant to PD-1/PD-L1 in chemoresistance in this review. PMID:26919108

  8. Chemotherapeutic effect of tangeretin, a polymethoxylated flavone studied in 7, 12-dimethylbenz(a)anthracene induced mammary carcinoma in experimental rats.

    PubMed

    Lakshmi, A; Subramanian, S

    2014-04-01

    Globally, breast cancer is the second most prevalent cancer among women and its incidence is amplifying alarmingly. Since genetics is believed to account for only 10% of the reported cases, the environmental factors including diet are thought to play a significant role in predisposing breast cancer. Many bioactive compounds of plant origin have been reported for their anticancer potential. Tangeretin, a pentamethoxy flavone, is a naturally occurring phytoconstituent found to be present in significant amounts in the peel of citrus fruits. Tangeretin possess a wide array of pharmacological activities such as cytostatic, anti-proliferative and antioxidant properties. In the absence of systemic studies in the literature, the present study was aimed to evaluate the chemotherapeutic potential of tangeretin in 7, 12-dimethyl benz(a)anthracene (DMBA) induced mammary carcinoma in rats. Oral treatment of tangeretin (50 mg/kg BW) to breast tumor bearing rats daily for four weeks was found to be effective against DMBA induced mammary gland carcinogenesis in female Wistar rats. The increased activities of AST, ALT, ALP, ACP, 5'-ND, γ-GT and LDH in serum of control and experimental breast cancer rats were significantly (p < 0.05) decreased to near normal levels. Further, the levels of lipid peroxide (TBARS), enzymatic antioxidants such as SOD, CAT, GPx and non-enzymatic antioxidants such as GSH, Vitamin C, Vitamin E and Phase I (cytochrome P450, cytochrome b5, EROD, MROD and PROD) and Phase II detoxification (glutathione S-transferase (GST), quinone reductase (QR)) were decreased significantly by administration of tangeretin. Immunohistochemical and western blotting studies for estrogen receptor, progesterone receptor and HER2/neu status exemplified the chemotherapeutic effect of tangeretin. Further, the histological and ultrastructural analysis of breast tissues evidenced the anti-tumorigenic nature of tangeretin. Thus, the results of the present study clearly indicate that

  9. Contrast agents for cardiac angiography: effects of a nonionic agent vs. a standard ionic agent

    SciTech Connect

    Bettmann, M.A.; Bourdillon, P.D.; Barry, W.H.; Brush, K.A.; Levin, D.C.

    1984-12-01

    The effects on cardiac hemodynamics and of a standard contrast agent, sodium methylglucamine diatrizoate (Renografin 76) were compared with the effects of a new nonionic agent (iohexol) in a double-blind study in 51 patietns undergoing coronary angiography and left ventriculography. No significant alteration in measured blood parameters occurred with either contrast agent. Hemodynamic changes occurred with both, but were significantly greater with the standard renografin than with the low-osmolality, nonionic iohexol. After left ventriculography, heart rate increased and peripheral arterial pressure fell with both agents, but less with iohexol. It is concluded that iohexol causes less alteration in cardiac function than does the agent currently most widely used. Nonionic contrast material is likely to improve the safety of coronary angiography, particularly in those patients at greatest risk.

  10. Antivasoconstrictor effect of the neuroprotective agent dexrazoxane in rat aorta.

    PubMed

    Vidrio, Horacio; Carrasco, Omar F; Rodríguez, Rodolfo

    2006-12-14

    Dexrazoxane is used clinically to reduce the cardiotoxicity of anthracycline cancer chemotherapeutic agents, acting by an iron-chelating antioxidant mechanism. In a study designed to explore the possible mechanism of the recently described neuroprotective effect of the drug in cerebral ischemia, its influence on vascular reactivity was determined in rat aortic rings. Dexrazoxane was found to be devoid of direct contractile or relaxant activity and to have no influence on responses to acetylcholine or histamine (relaxation), or to angiotensin or serotonin (contraction). In contrast, it decreased contractions to norepinephrine, as evidenced by rightward displacement of the concentration-response curves. The effect was prevented by the removal of the endothelium and by the alpha(2)-adrenoceptor antagonist yohimbine; it was partially antagonized by the endothelium-derived depolarizing factor inhibitor clotrimazole, but was not affected by L-NAME or indomethacin, inhibitors of endothelial nitric oxide and prostacyclin production. The anti-contractile effect did not occur in rings stimulated with the alpha(1)-adrenoceptor agonist phenylephrine. It was concluded that dexrazoxane opposes norepinephrine vascular contraction by enhancing endothelial alpha(2)-adrenoceptor-mediated release of relaxing factor(s). The drug could thus offset the deleterious vasoconstriction elicited by the increased circulating catecholamines present during cerebral ischemia, and by this mechanism produce neuroprotection.

  11. Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human Colorectal Cancer Stem Cells by Inducing Differentiation

    PubMed Central

    Kim, Buyun

    2016-01-01

    Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and chemo-resistance properties in various tumors including colorectal cancer. Targeting of CSCs may be essential to prevent relapse of tumors after chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signals are central regulators of cell growth, proliferation, differentiation, and apoptosis. These pathways are related to colorectal tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which initiate differentiation of SW620 derived CSCs and investigated its effect on tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. Colorectal CSCs gained their differentiation property and lost their stemness properties most significantly in dual-blocked CSCs. After treated with anti-cancer drug (paclitaxel) on the differentiated CSCs cell viability, self-renewal ability and differentiation status were analyzed. As a result dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited group more effectively increased drug sensitivity and suppressed tumor growth compared to single-inhibited groups. Therefore it could have potent anti-cancer effects that dual-blocking of PI3K and mTOR induces differentiation and improves chemotherapeutic effects on SW620 human colorectal CSCs. PMID:26955235

  12. Local bacteria affect the efficacy of chemotherapeutic drugs

    PubMed Central

    Lehouritis, Panos; Cummins, Joanne; Stanton, Michael; Murphy, Carola T.; McCarthy, Florence O.; Reid, Gregor; Urbaniak, Camilla; Byrne, William L.; Tangney, Mark

    2015-01-01

    In this study, the potential effects of bacteria on the efficacy of frequently used chemotherapies was examined. Bacteria and cancer cell lines were examined in vitro and in vivo for changes in the efficacy of cancer cell killing mediated by chemotherapeutic agents. Of 30 drugs examined in vitro, the efficacy of 10 was found to be significantly inhibited by certain bacteria, while the same bacteria improved the efficacy of six others. HPLC and mass spectrometry analyses of sample drugs (gemcitabine, fludarabine, cladribine, CB1954) demonstrated modification of drug chemical structure. The chemoresistance or increased cytotoxicity observed in vitro with sample drugs (gemcitabine and CB1954) was replicated in in vivo murine subcutaneous tumour models. These findings suggest that bacterial presence in the body due to systemic or local infection may influence tumour responses or off-target toxicity during chemotherapy. PMID:26416623

  13. Does an Agent Matter? The Effects of Animated Pedagogical Agents on Multimedia Environments.

    ERIC Educational Resources Information Center

    Craig, Scotty D.; Gholson, Barry

    Data are presented on the effects of Animated Agents on multimedia learning environments with specific concerns of split attention and modality effects. The study was a 3 (agent properties: agent only, agent with gestures, no agent) x 3 (picture features: static picture, sudden onset, animation) factorial design with outcome measures of mental…

  14. Effects of exogenous agents on brain development: stress, abuse and therapeutic compounds.

    PubMed

    Archer, Trevor

    2011-10-01

    The range of exogenous agents likely to affect, generally detrimentally, the normal development of the brain and central nervous system defies estimation although the amount of accumulated evidence is enormous. The present review is limited to certain types of chemotherapeutic and "use-and-abuse" compounds and environmental agents, exemplified by anesthetic, antiepileptic, sleep-inducing and anxiolytic compounds, nicotine and alcohol, and stress as well as agents of infection; each of these agents have been investigated quite extensively and have been shown to contribute to the etiopathogenesis of serious neuropsychiatric disorders. To greater or lesser extent, all of the exogenous agents discussed in the present treatise have been investigated for their influence upon neurodevelopmental processes during the period of the brain growth spurt and during other phases uptill adulthood, thereby maintaining the notion of critical phases for the outcome of treatment whether prenatal, postnatal, or adolescent. Several of these agents have contributed to the developmental disruptions underlying structural and functional brain abnormalities that are observed in the symptom and biomarker profiles of the schizophrenia spectrum disorders and the fetal alcohol spectrum disorders. In each case, the effects of the exogenous agents upon the status of the affected brain, within defined parameters and conditions, is generally permanent and irreversible.

  15. Melanoma targeting with the loco-regional chemotherapeutic, Melphalan: From cell death to immunotherapeutic efficacy.

    PubMed

    Dudek-Perić, Aleksandra Maria; Gołąb, Jakub; Garg, Abhishek D; Agostinis, Patrizia

    2015-12-01

    All immunoregulatory chemotherapeutics are chiefly applied in a systemic setting for anticancer therapy. However, immune responses following loco-regional application of chemotherapy may differ from those after systemic application. We recently found that Melphalan, a prototypical loco-regionally applied chemotherapeutic agent, exhibits the ability to increase the immunogenicity of dying melanoma cells.

  16. The significance of the C-reactive protein to albumin ratio as a marker for predicting survival and monitoring chemotherapeutic effectiveness in patients with unresectable metastatic colorectal cancer.

    PubMed

    Shibutani, Masatsune; Maeda, Kiyoshi; Nagahara, Hisashi; Iseki, Yasuhito; Hirakawa, Kosei; Ohira, Masaichi

    2016-01-01

    Inflammation has been reported to play an important role in cancer progression and various inflammatory markers have been reported to be useful prognostic markers. The aim of this retrospective study was to evaluate the significance of the C-reactive protein to albumin (CRP/ALB) ratio in colorectal cancer patients who received palliative chemotherapy. We performed a retrospective review of 99 patients who underwent palliative chemotherapy for unresectable colorectal cancer between 2005 and 2010. The cutoff value of the CRP/ALB ratio was determined based on a receiver operating characteristics curve analysis. The relationship between the CRP/ALB ratio and survival was assessed. The cutoff value for the CRP/ALB ratio was 0.183. The high pretreatment CRP/ALB ratio group showed significantly worse overall survival. Patients with a high pretreatment CRP/ALB ratio and in whom the CRP/ALB ratio normalized after chemotherapy tended to have better overall survival than those in whom both the pretreatment and posttreatment CRP/ALB ratios were high. The CRP/ALB ratio is a useful marker for predicting survival and monitoring chemotherapeutic effectiveness in patients with unresectable metastatic colorectal cancer.

  17. Grape Seed Extract Dose-Responsively Decreases Disease Severity in a Rat Model of Mucositis; Concomitantly Enhancing Chemotherapeutic Effectiveness in Colon Cancer Cells

    PubMed Central

    Cheah, Ker Yeaw; Howarth, Gordon Stanley; Bastian, Susan Elaine Putnam

    2014-01-01

    Objective Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells. Design Female Dark Agouti rats were gavaged with grape seed extract (400–1000 mg/kg) or water (day 3–11) and were injected intraperitoneally with 5-Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5-Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) assay. Results Compared with 5-Fluorouracil controls, grape seed extract (400–1000 mg/kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. Grape seed extract was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum. Grape seed extract (10–25 ug/mL) significantly enhanced the growth-inhibitory effects of 5-Fluorouracil by 26% (P<0.05) in Caco-2 cells and was more potent than 5-Fluorouracil at 50–100 µg/mL. Conclusion Grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells. PMID:24465501

  18. Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells

    PubMed Central

    Miao, Xin; Koch, Gilbert; Straubinger, Robert M.

    2015-01-01

    Purpose This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions. Methods Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter ψ was used to quantify the effects of the individual drugs and combinations. Results Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant Kmax and the sensitivity constant KC50) for each drug. The interaction parameter ψ was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects. Conclusions The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations. PMID:26604207

  19. Chemopreventive and chemotherapeutic effects of genistein, a soy isoflavone, upon cancer development and progression in preclinical animal models

    PubMed Central

    Kim, Seung-Hee; Kim, Cho-Won; Jeon, So-Ye; Go, Ryeo-Eun

    2014-01-01

    Genistein is one of isoflavones mostly derived in a leguminous plant. It is well known as one of phytoestrogens that have structures similar to the principal mammalian estrogen. It has diverse biological functions including chemopreventive properties against cancers. Anticancer efficacies of genistein have been related with the epidemiological observations indicating that the incidence of some cancers is much lower in Asia, where diets are rich in soyfoods, than Western countries. This review deals with in vivo anticancer activities of genistein identified in animal studies being divided into its effects on carcinogenesis and cancer progression. Because animal studies have advantages in designing the experiments to suit the goals, they imply diverse information on the anticancer activity of genistein. The in vivo animal studies have adopted the specific animal models according to a developmental stage of cancer to prove the anticancer efficacies of genistein against diverse types of cancer. The numerous previous studies insist that genistein effectively inhibits carcinogenesis in the DMBA-induced animal cancer models by reducing the incidence of adenocarcinoma and cancer progression in the transgenic and xenograft animal models by suppressing the tumor growth and metastatic transition. Although the protective effect of genistein against cancer has been controversial, genistein may be a candidate for chemoprevention of carcinogenesis and cancer progression and may deserve to be the central compound supporting the epidemiological evidence. PMID:25628724

  20. Oxidative stress triggered by naturally occurring flavone apigenin results in senescence and chemotherapeutic effect in human colorectal cancer cells.

    PubMed

    Banerjee, Kacoli; Mandal, Mahitosh

    2015-08-01

    Recent studies involving phytochemical polyphenolic compounds have suggested flavones often exert pro-oxidative effect in vitro against wide array of cancer cell lines. The aim of this study was to evaluate the in-vitro pro-oxidative activity of apigenin, a plant based flavone against colorectal cancer cell lines and investigate cumulative effect on long term exposure. In the present study, treatment of colorectal cell lines HT-29 and HCT-15 with apigenin resulted in anti-proliferative and apoptotic effects characterized by biochemical and morphological changes, including loss of mitochondrial membrane potential which aided in reversing the impaired apoptotic machinery leading to negative implications in cancer pathogenesis. Apigenin induces rapid free radical species production and the level of oxidative damage was assessed by qualitative and quantitative estimation of biochemical markers of oxidative stress. Increased level of mitochondrial superoxide suggested dose dependent mitochondrial oxidative damage which was generated by disruption in anti-apoptotic and pro-apoptotic protein balance. Continuous and persistent oxidative stress induced by apigenin at growth suppressive doses over extended treatment time period was observed to induce senescence which is a natural cellular mechanism to attenuate tumor formation. Senescence phenotype inducted by apigenin was attributed to changes in key molecules involved in p16-Rb and p53 independent p21 signaling pathways. Phosphorylation of retinoblastoma was inhibited and significant up-regulation of p21 led to simultaneous suppression of cyclins D1 and E which indicated the onset of senescence. Pro-oxidative stress induced premature senescence mediated by apigenin makes this treatment regimen a potential chemopreventive strategy and an in vitro model for aging research.

  1. ZEB1 knockdown mediated using polypeptide cationic micelles inhibits metastasis and effects sensitization to a chemotherapeutic drug for cancer therapy

    NASA Astrophysics Data System (ADS)

    Fang, Shengtao; Wu, Lei; Li, Mingxing; Yi, Huqiang; Gao, Guanhui; Sheng, Zonghai; Gong, Ping; Ma, Yifan; Cai, Lintao

    2014-08-01

    Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced metastasis in the lung. When DOX and siRNA were co-delivered by the nanocarriers (siRNA-DOX-NP), a synergistic therapeutic effect was observed, resulting in dramatic inhibition of tumor growth in a H460 xenograft model. These results demonstrated that the siRNA-NP or siRNA-DOX-NP complex targeting ZEB1 could be developed into a new therapeutic approach for non-small cell lung cancer (NSCLC) treatment.Metastasis and drug resistance are the main causes for the failure in clinical cancer therapy. Emerging evidence suggests an intricate role of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in metastasis and drug resistance. The EMT-activator ZEB1 is crucial in malignant tumor progression by linking EMT-activation and stemness-maintenance. Here, we used multifunctional polypeptide micelle nanoparticles (NP) as nanocarriers for the delivery of ZEB1 siRNA and doxorubicin (DOX). The nanocarriers could effectively deliver siRNA to the cytoplasm and knockdown the target gene in H460 cells and H460 xenograft tumors, leading to reduced EMT and repressed CSC properties in vitro and in vivo. The complex micelle nanoparticles with ZEB1 siRNA (siRNA-NP) significantly reduced

  2. Reductions in genetic diversity of Schistosoma mansoni populations under chemotherapeutic pressure: the effect of sampling approach and parasite population definition.

    PubMed

    French, Michael D; Churcher, Thomas S; Basáñez, María-Gloria; Norton, Alice J; Lwambo, Nicholas J S; Webster, Joanne P

    2013-11-01

    Detecting potential changes in genetic diversity in schistosome populations following chemotherapy with praziquantel (PZQ) is crucial if we are to fully understand the impact of such chemotherapy with respect to the potential emergence of resistance and/or other evolutionary outcomes of interventions. Doing so by implementing effective, and cost-efficient sampling protocols will help to optimise time and financial resources, particularly relevant to a disease such as schistosomiasis currently reliant on a single available drug. Here we explore the effect on measures of parasite genetic diversity of applying various field sampling approaches, both in terms of the number of (human) hosts sampled and the number of transmission stages (miracidia) sampled per host for a Schistosoma mansoni population in Tanzania pre- and post-treatment with PZQ. In addition, we explore population structuring within and between hosts by comparing the estimates of genetic diversity obtained assuming a 'component population' approach with those using an 'infrapopulation' approach. We found that increasing the number of hosts sampled, rather than the number of miracidia per host, gives more robust estimates of genetic diversity. We also found statistically significant population structuring (using Wright's F-statistics) and significant differences in the measures of genetic diversity depending on the parasite population definition. The relative advantages, disadvantages and, hence, subsequent reliability of these metrics for parasites with complex life-cycles are discussed, both for the specific epidemiological and ecological scenario under study here and for their future application to other areas and schistosome species.

  3. Dietary phytochemicals as potent chemotherapeutic agents against breast cancer: Inhibition of NF-κB pathway via molecular interactions in rel homology domain of its precursor protein p105

    PubMed Central

    Khan, Mohammad K. A.; Ansari, Irfan A.; Khan, M. Salman; Arif, Jamal M.

    2013-01-01

    Background: Dietary phytochemicals consist of a wide variety of biologically active compounds that are ubiquitous in plants, many of which have been reported to have anti-tumor as well as anti-inflammatory properties. Objective: In the present study, we aimed to validate these findings by using docking protocols and explicate the possible mechanism of action for a dataset of nine phytochemicals namely boswellic acid, 1-caffeoylquinic acid, ellagic acid, emodin, genistein, guggulsterone, quercetin, resveratrol, and sylibinin from different plants against the nuclear factor- kappaB (NF-κB) precursor protein p105, an important transcription factor reported to be overexpressed in breast cancer. Materials and Methods: 2-D structures of all phytochemicals were retrieved from PubChem Compound database and their subsequent conversion into 3-D structures was performed by using online software system CORINA. The X-ray crystallographic structure of the NF-κB precursor p105 was extracted from Brookhaven Protein Data Bank. Molecular docking simulation study was carried out by using AutoDock Tools 4.0. Results: Our results showed significant binding affinity of different phytochemicals with the Rel homology domain of the NF-κB precursor protein p105. Quercetin and 1-caffeoylquinic acid were found to be very effective inhibitors against target molecule as they showed binding energy of −12.11 and −11.50 Kcal/mol, respectively. The order of affinity of other ligands with p105 was found as follows: guggulsterone > sylibinin > emodin > resveratrol > genistein > boswellic acid > ellagic acid. Conclusion: Our in silico study has explored the possible chemopreventive mechanism of these phytochemicals against the NF-κB precursor protein p105 and deciphered that quercetin, 1-caffeoylquinic acid and guggulsterone were the potent inhibitors against target molecule. In addition, large scale preclinical and clinical trials are needed to explore the role of these chemotherapeutic

  4. The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice

    SciTech Connect

    Hirose, Aya; Sato, Eri; Fujii, Hajime; Sun Buxiang; Nishioka, Hiroshi . E-mail: nishioka@aminoup.co.jp; Aruoma, Okezie I. . E-mail: okezie.aruoma@touro.edu

    2007-07-15

    Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p < 0.05) and weight (p < 0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with

  5. Receptor for advanced glycation end product blockade enhances the chemotherapeutic effect of cisplatin in tongue squamous cell carcinoma by reducing autophagy and modulating the Wnt pathway.

    PubMed

    Zhao, Ziming; Wang, Hongyu; Zhang, Liao; Mei, Xifan; Hu, Jing; Huang, Keqiang

    2017-02-01

    Tongue squamous cell carcinoma (TSCC) is one of the most severe types of cancer with poor outcomes. Cisplatin is used widely to treat cancer cells, but many patients develop acquired drug resistance. The receptor for advanced glycation end products (RAGE) is expressed widely in TSCC and associated with drug-induced chemotherapy resistance. However, the effect of RAGE and cisplatin on Tca-8113 cells remains unknown. We assayed the combined use of RAGE blockade and cisplatin effect on Tca-8113 cells' viability by MTT and apoptosis rate of Tca-8113 cells on RAGE blockade+cisplatin treatment; cisplatin alone; or RAGE blockade alone by flow cytometry. We observed the expressions of autophagy-related proteins beclin1, LC3II, p62; Wnt signaling-related proteins β-catenin, GSK3β, WNT5A, ROR-2; and apoptosis-related protein cleaved caspase-3, bcl-2-associated X proteins using western blot. We determined WNT5A and beclin1 expression on Tca-8113 cells by immunofluorescence. We further observed autophagy vacuoles by monodansylcadaverine staining. We found that RAGE blockade and cisplatin significantly decreased cell viability and increased the cell apoptosis rate compared with cisplatin alone. Furthermore, RAGE blockade suppressed the canonical Wnt pathway proteins β-catenin and GSK-3β, but upregulated noncanonical WNT5A and receptor ROR-2. We show that RAGE blockade suppressed the levels of autophagy-related protein LC3II/I, beclin1, accelerated degradation of autophagy for the increasing p62 expression, and increased cell apoptosis for the increasing expressions of cleaved caspase-3 and bcl-2-associated X proteins. We observed the location of WNT5A and beclin1 expressions on cells by immunofluorescence and their trends were consistent with western blotting. Taken together, our findings suggested that RAGE blockade+cisplatin improved chemotherapeutic effects by reducing autophagy and regulating Wnt/β-catenin to suppress the progression of TSCC.

  6. Effects of Agent Transparency on Multi-Robot Management Effectiveness

    DTIC Science & Technology

    2015-09-01

    war” with its inherent complex, ambiguous, and time -challenged conditions. Mission effectiveness will rely on rapid identification and management of...ARL-TR-7466 ● SEP 2015 US Army Research Laboratory Effects of Agent Transparency on Multi-Robot Management Effectiveness by...SEP 2015 US Army Research Laboratory Effects of Agent Transparency on Multi-Robot Management Effectiveness by Joseph E Mercado Oak

  7. Some characteristics of activity of potential chemotherapeutics--benzimidazole derivatives.

    PubMed

    Błaszczak-Świątkiewicz, Katarzyna; Mikiciuk-Olasik, Elżbieta

    2015-03-01

    In this work, the biological activity of some benzimidazoles and benzimidazole-4,7-diones was compared. These two groups of compounds were evaluated as potential chemotherapeutics and their characteristic relationship structure to biological activity was discussed. The authors compared their effect into the cytotoxic, apoptosis and DNA destruction approach. Their cytotoxic effect on the human lung adenocarcinoma A549 cells line was determined by WST-1 test. Next the cytotoxic way of tumor cells death was determined by caspase 3/7 test. The last point referred to the DNA destruction of A549 cells and test in situ DNA Assay Kit was applied. Two of the examined compounds (B2 and D2) show a very good correlation of the cytotoxic effect normoxia to hypoxia and they have been found as the potential agents of the DNA damage. The most cytotoxic feature possesses N-oxide benzimidazole derivatives (D and B groups). The screening test of the DNA damage established that N-oxide benzimidazole derivatives (D and B groups) can be more potent as the hypoxia-selective agents for tumor cells than benzimidazole derivatives (A and C groups). Additionally, the test of the caspase-dependent apoptosis proved that the exposure of benzimidazole-4,7-diones against A549 cells, especially in hypoxia, promotes apoptotic cell death.

  8. Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma

    PubMed Central

    Hong, Ji Eun; Cho, Young Jae; Ryu, Ji Yoon; Choi, Jung-Joo; Lee, Sang Hoon; Yoon, Gun; Kim, Woo Young; Do, In-Gu; Kim, Min Kyu; Kim, Tae-Joong; Choi, Chel Hun; Lee, Jeong-Won; Bae, Duk-Soo; Kim, Byoung-Gie

    2015-01-01

    This study was designed to investigate whether proton pump inhibitors (PPI, V-ATPase blocker) could increase the effect of cytotoxic agents in chemoresistant epithelial ovarian cancer (EOC). Expression of V-ATPase protein was evaluated in patients with EOC using immunohistochemistry, and patient survival was compared based on expression of V-ATPase mRNA from a TCGA data set. In vitro, EOC cell lines were treated with chemotherapeutic agents with or without V-ATPase siRNA or PPI (omeprazole) pretreatment. Cell survival and apoptosis was assessed using MTT assay and ELISA, respectively. In vivo experiments were performed to confirm the synergistic effect with omeprazole and paclitaxel on tumor growth in orthotopic and patient-derived xenograft (PDX) mouse models. Expression of V-ATPase protein in ovarian cancer tissues was observed in 44 patients (44/59, 74.6%). Higher expression of V-ATPase mRNA was associated with poorer overall survival in TCGA data. Inhibition of V-ATPase by siRNA or omeprazole significantly increased cytotoxicity or apoptosis to paclitaxel in chemoresistant (HeyA8-MDR, SKOV3-TR) and clear cell carcinoma cells (ES-2, RMG-1), but not in chemosensitive cells (HeyA8, SKOV3ip1). Moreover, the combination of omeprazole and paclitaxel significantly decreased the total tumor weight compared with paclitaxel alone in a chemoresistant EOC animal model and a PDX model of clear cell carcinoma. However, this finding was not observed in chemosensitive EOC animal models. These results show that omeprazole pretreatment can increase the effect of chemotherapeutic agents in chemoresistant EOC and clear cell carcinoma via reduction of the acidic tumor microenvironment. PMID:26418900

  9. Effects of HGF gene polymorphisms and protein expression on transhepatic arterial chemotherapeutic embolism efficacy and prognosis in patients with primary liver cancer

    PubMed Central

    Chen, Hai-Yong; Chen, Yao-Min; Wu, Jian; Yang, Fu-Chun; Lv, Zhen; Qian, Yi-Gang; Zheng, Shu-Sen

    2017-01-01

    Objective To investigate the correlations of two hepatocyte growth factor (HGF) gene polymorphisms (rs5745652 and rs2074725) and their protein expression levels with the efficacy of transhepatic arterial chemotherapeutic embolism (TACE) and prognosis in patients with primary liver cancer (PLC). Methods From March 2011 to June 2012, 109 PLC patients (the case group) who chose TACE as primary treatment and 80 healthy people (the control group) who had undergone physical examination in The First Affiliated Hospital, Zhejiang University were selected during the same period. Gene polymorphisms of HGF rs5745652 and HGF rs2074725 were detected. Serum HGF level, treating efficacy, survival quality, and 3-year survival rate for PLC patients who received TACE were observed. Results There were significant differences in genotype and allele frequencies of HGF rs5745652 and HGF rs2074725, between the case and control groups (all P<0.05). Compared with CT+TT genotype of HGF rs5745652, patients carrying CC genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate (all P<0.05). In rs2074725, patients carrying CA+AA genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate compared with patients carrying rs2074725 CC genotype (all P<0.05). Gene polymorphisms of HGF rs5745652 and HGF rs2074725, tumor size, and Barcelona Clinic Liver Cancer stage were independent prognostic factors for PLC (P<0.05). Conclusion Our results indicated that HGF gene polymorphisms affect TACE efficacy and survival quality of PLC patients. Patients with HGF CC genotype of rs5745652 and CA+AA genotype of rs2074725 had decreased HGF level, better curative effect, high survival quality, and a good prognosis after TACE treatment. PMID:28243116

  10. Xenon fluoride solutions effective as fluorinating agents

    NASA Technical Reports Server (NTRS)

    Hyman, H. H.; Quarterman, L. A.; Sheft, I.

    1967-01-01

    Solutions of xenon fluorides in anhydrous hydrogen fluoride have few disruptive effects and leave a residue consisting of gaseous xenon, which can be recovered and refluorinated. This mild agent can be used with materials which normally must be fluorinated with fluorine alone at high temperatures.

  11. Development of a novel, physiologically relevant cytotoxicity model: Application to the study of chemotherapeutic damage to mesenchymal stromal cells

    SciTech Connect

    May, Jennifer E. Morse, H. Ruth Xu, Jinsheng Donaldson, Craig

    2012-09-15

    There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated. In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co-culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy. Minimal modifications would enable this novel co-culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in-vitro study. -- Highlights: ► An in vitro model was developed for study of drugs requiring hepatic metabolism ► HepG2 spheroids were utilised as a physiologically relevant source of liver enzymes ► The model was optimised to enable study of chemotherapeutic

  12. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: The role of inflammation

    PubMed Central

    Lee, Chun Seng; Ryan, Elizabeth J; Doherty, Glen A

    2014-01-01

    Chemotherapy-induced diarrhea (CID) is a common and often severe side effect experienced by colorectal cancer (CRC) patients during their treatment. As chemotherapy regimens evolve to include more efficacious agents, CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation. Inflammation is a key factor behind gastrointestinal (GI) toxicity of chemotherapy. Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa. Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC. Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed. The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity, thus conferring added benefit against tumor recurrence and improving patient survival. We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer. Finally, the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed. PMID:24744571

  13. Clinical effectiveness of contemporary dentin bonding agents

    PubMed Central

    Krithikadatta, Jogikalmat

    2010-01-01

    Aim: The purpose of this paper is to review the literature on the clinical effectiveness of contemporary resin-based dentin bonding agents primarily focussing on the longevity of restoration. Materials and Methods: The literature published from June 2004 up to September 2010 was reviewed for clinical trials that tested the effectiveness of dentin bonding agents in the longevity of noncarious class V restoration. Results of each study reported using the USPHS criteria for clinical assessment of restoration were included and tabulated. The American Dental Association guidelines for dentin and enamel adhesives were used as a reference to compare the performance of individual bonding agents. Kruskal–Wallis followed by Mann–Whitney U was done to compare the mean Alfa score percentage for the three categories of bonding systems [etch-and-rinse (ER), self-etch primer (SEP), and self-etch-adhesive (SEA)]. Results: A comparison of the mean Alfa score percentages revealed no difference between the ER, SEP, and SEA categories of bonding systems except for marginal adaptation where ER was found to be superior to SEA. Conclusion: The clinical effectiveness of resin-based bonding agents is comparable among the three categories. PMID:21217944

  14. Lipid biosynthesis pathways as chemotherapeutic targets in kinetoplastid parasites.

    PubMed

    Urbina, J A

    1997-01-01

    Inhibitors of sterol and phospholipid biosynthesis in kinetoplastid parasites such as Trypanosoma cruzi, the causative agent of Chagas' disease, and different species of Leishmania have potent and selective activity as chemotherapeutic agents in vitro and in vivo. Recent work with the sterol C14 alpha-demethylase inhibitor D0870, a bis triazole derivative, showed that this compound is capable of inducing radical parasitological cure in murine models of both acute and chronic Chagas' disease. Other inhibitors of this type, such as SCH 56592, have also shown curative, rather than suppressive, activity against T. cruzi in these models. Leishmania species have different susceptibilities to sterol biosynthesis inhibitors, both in vitro and in vivo. Leishmania braziliensis promastigotes, naturally resistant to C14 alpha-demethylase inhibitors such as ketoconazole and D0870, were susceptible to these drugs when used in combination with the squalene epoxidase inhibitor terbinafine. Inhibitors of delta 24(25) sterol methyl transferase have been shown to act as potent antiproliferative agents against Trypanosoma cruzi, both in vitro and in vivo. New inhibitors of this type which show enhanced activity and novel mechanisms of action have been synthesized. Recent work has also demonstrated that this type of enzyme inhibitors can block sterol biosynthesis and cell proliferation in Pneumocystis carinii, a fungal pathogen which had previously been found resistant to other sterol biosynthesis inhibitors. Ajoene, an antiplatelet compound derived from garlic, was shown to have potent antiproliferative activity against epimastigotes and amastigotes of Trypanosoma cruzi in vitro; this activity was associated with a significant alteration of the phospholipid composition of the cells with no significant effects on the sterol content. In addition, alkyllsophospholipids such as ilmofosine, miltefosine and edelfosine have been shown to block the proliferation of T. cruzi and Leishmania and

  15. A minimum core outcome dataset for the reporting of preclinical chemotherapeutic drug studies: Lessons learned from multiple discordant methodologies in the setting of colorectal cancer.

    PubMed

    West, M A; Roman, A; Sayan, E; Primrose, J N; Wedge, S R; Underwood, T J; Mirnezami, A H

    2017-04-01

    In vivo studies in animal models are critical tools necessary to study the fundamental complexity of carcinogenesis. A constant strive to improve animal models in cancer exists, especially those investigating the use of chemotherapeutic effectiveness. In the present systematic review, colorectal cancer (CRC) is used as an example to highlight and critically evaluate the range of reporting strategies used when investigating chemotherapeutic agents in the preclinical setting. A systematic review examining the methodology and reporting of preclinical chemotherapeutic drug studies using CRC murine models was conducted. A total of 45 studies were included in this systematic review. The literature was found to be highly heterogeneous with various cell lines, animal strains, animal ages and chemotherapeutic compounds/regimens tested, proving difficult to compare outcomes between similar studies or indeed gain any significant insight into which chemotherapeutic regimen caused adverse events. From this analysis we propose a minimum core outcome dataset that could be regarded as a standardised way of reporting results from in vivo experimentation.

  16. A novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells

    PubMed Central

    Wang, Si; Placzek, William J.; Stebbins, John L.; Mitra, Sayantan; Noberini, Roberta; Koolpe, Mitchell; Zhang, Ziming; Dahl, Russell; Pasquale, Elena B.; Pellecchia, Maurizio

    2012-01-01

    The efficacy of anti-cancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is over-expressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anti-cancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found that the peptide-drug conjugate is dramatically more effective than paclitaxel alone at inhibiting tumor growth in a prostate cancer xenograft model, delivering significantly higher levels of drug to the tumor site. We believe these studies open the way to the development of a new class of therapeutic compounds that exploit the EphA2 receptor for drug delivery to cancer cells. PMID:22329578

  17. The Use of Chemotherapeutics for the Treatment of Keloid Scars

    PubMed Central

    Jones, Christopher David; Guiot, Luke; Samy, Mike; Gorman, Mark; Tehrani, Hamid

    2015-01-01

    Keloid scars are pathological scars, which develop as a result of exaggerated dermal tissue proliferation following cutaneous injury and often cause physical, psychological and cosmetic problems. Various theories regarding keloidogenesis exist, however the precise pathophysiological events remain unclear. Many different treatment modalities have been implicated in their management, but currently there is no entirely satisfactory method for treating all keloid lesions. We review a number of different chemotherapeutic agents which have been proposed for the treatment of keloid and hypertrophic scars while giving insight into some of the novel chemotherapeutic drugs which are currently being investigated. Non-randomized trials evaluating the influence of different chemotherapeutic agents, such as 5-fluorouracil (5-FU); mitomycin C; bleomycin and steroid injection, either alone or in combination with other chemotherapeutic agents or alternative treatment modalities, for the treatment of keloids were identified using a predefined PubMed search strategy. Twenty seven papers were identified. Scar improvement ≥50% was found in the majority of cases treated with 5-FU, with similar results found for mitomycin C, bleomycin and steroid injection. Combined intralesional 5-FU and steroid injection produced statistically significant improvements when compared to monotherapy. Monotherapy recurrence rates ranged from 0-47% for 5-FU, 0-15% for bleomycin and 0-50% for steroid injection. However, combined therapy in the form of surgical excision and adjuvant 5-FU or steroid injections demonstrated lower recurrence rates; 19% and 6% respectively. Currently, most of the literature supports the use of combination therapy (usually surgery and adjuvant chemotherapy) as the mainstay treatment of keloids, however further investigation is necessary to determine success rates over longer time frames. Furthermore, there is the potential for novel therapies, but further investigation is

  18. Comparative sporicidal effects of liquid chemical agents.

    PubMed Central

    Sagripanti, J L; Bonifacino, A

    1996-01-01

    We compared the effectiveness of glutaraldehyde, formaldehyde, hydrogen peroxide, peracetic acid, cupric ascorbate (plus a sublethal amount of hydrogen peroxide), sodium hypochlorite, and phenol to inactivate Bacillus subtilis spores under various conditions. Each chemical agent was distinctly affected by pH, storage time after activation, dilution, and temperature. Only three of the preparations (hypochlorite, peracetic acid, and cupric ascorbate) studied here inactivated more than 99.9% of the spore load after a 30-min incubation at 20 degrees C at concentrations generally used to decontaminate medical devices. Under similar conditions, glutaraldehyde inactivated approximately 90%, and hydrogen peroxide, formaldehyde, and phenol produced little killing of spores in suspension. By kinetic analysis at different temperatures, we calculated the rate of spore inactivation (k) and the activation energy of spore killing (delta E) for each chemical agent. Rates of spore inactivation had a similar delta E value of approximately 20 kcal/mol (ca.83.68 kJ/mol) for every substance tested. The variation among k values allowed a quantitative comparison of liquid germicidal agents. PMID:8593054

  19. Cell Membrane Capsules for Encapsulation of Chemotherapeutic and Cancer Cell Targeting in Vivo.

    PubMed

    Peng, Li-Hua; Zhang, Yuan-Hong; Han, Li-Jie; Zhang, Chen-Zhen; Wu, Jia-He; Wang, Xia-Rong; Gao, Jian-Qing; Mao, Zheng-Wei

    2015-08-26

    Systemic administration of chemotherapeutic agents can cause indiscriminate drug distribution and severe toxicity. Until now, encapsulation and targeting of drugs have typically relied on synthetic vehicles, which cannot minimize the clearance by the renal system and may also increase the risk of chemical side effects. Cell membrane capsules (CMCs) provide a generic and far more natural approach to the challenges of drug encapsulation and delivery in vivo. Here aptamer AS1411, which can recognize and bind overexpressed nucleolin on a cancer cell membrane, was chemically conjugated onto CMCs. As a result, AS1411 modified CMCs showed enhanced ingestion in certain cancer cells in vitro and accumulation in mouse cancer xenografts in vivo. Chemotherapeutics and contrast agents with therapeutically significant concentrations can be packaged into CMCs by reversible permeating their plasma membranes. The systematic administration of cancer targeting CMCs loaded with doxorubicin hydrochloride can significantly inhibit tumor growth in mouse xenografts, with significantly reduced toxicity compared to free drug. These findings suggest that cancer targeting CMCs may have considerable benefits in drug delivery and cancer treatment.

  20. Combination of conventional chemotherapeutics with redox-active cerium oxide nanoparticles--a novel aspect in cancer therapy.

    PubMed

    Sack, Maren; Alili, Lirija; Karaman, Elif; Das, Soumen; Gupta, Ankur; Seal, Sudipta; Brenneisen, Peter

    2014-07-01

    Nanotechnology is becoming an important field of biomedical and clinical research and the application of nanoparticles in disease may offer promising advances in treatment of many diseases, especially cancer. Malignant melanoma is one of the most aggressive forms of cancer and its incidence is rapidly increasing. Redox-active cerium oxide nanoparticles (CNP) are known to exhibit significant antitumor activity in cells derived from human skin tumors in vitro and in vivo, whereas CNP is nontoxic and beyond that even protective (antioxidative) in normal, healthy cells of the skin. As the application of conventional chemotherapeutics is associated with harmful side effects on healthy cells and tissues, the clinical use is restricted. In this study, we addressed the question of whether CNP supplement a classical chemotherapy, thereby enhancing its efficiency without additional damage to normal cells. The anthracycline doxorubicin, one of the most effective cancer drugs, was chosen as reference for a classical chemotherapeutic agent in this study. Herein, we show that CNP enhance the antitumor activity of doxorubicin in human melanoma cells. Synergistic effects on cytotoxicity, reactive oxygen species generation, and oxidative damage in tumor cells were observed after co-incubation. In contrast to doxorubicin, CNP do not cause DNA damage and even protect human dermal fibroblasts from doxorubicin-induced cytotoxicity. A combination of classical chemotherapeutics with nongenotoxic but antitumor active CNP may provide a new strategy against cancer by improving therapeutic outcome and benefit for patients.

  1. Alkaloids of fascaplysin are effective conventional chemotherapeutic drugs, inhibiting the proliferation of C6 glioma cells and causing their death in vitro

    PubMed Central

    Bryukhovetskiy, Igor; Lyakhova, Irina; Mischenko, Polina; Milkina, Elena ; Zaitsev, Sergei ; Khotimchenko, Yuri; Bryukhovetskiy, Andrey; Polevshchikov, Alexander ; Kudryavtsev, Igor; Khotimchenko, Maxim; Zhidkov, Maxim

    2017-01-01

    Glioblastoma multiforme is an invasive malignant glial brain tumor with a poor prognosis for patients. The primary reasons that lead to the development of treatment resistance are associated with tumor cells infiltrating the brain parenchyma and the specific properties of tumor stem cells. A crucial research area in medical science is the search for effective agents that are able to act on these targets. Fascaplysin alkaloids possess potent antitumor activity. Modern methods for the targeted delivery of drugs reveal extensive possibilities in terms of the clinical use of these compounds. The aim of the present study was to establish effective concentrations of fascaplysin that inhibit the growth and kill the cells of glial tumors, as well as to perform a comparative analysis of fascaplysin's effectiveness in relation to other chemotherapy drugs. C6 glioma cells were utilized as an optimal model of glioblastoma. It was established that fascaplysin at 0.5 µM has a strong cytotoxic effect, which is subsequently replaced by tumor cell death via apoptosis as the length of drug exposure time is increased. Fascaplysin kills glioma cells at a dose higher than 0.5 µM. The efficiency of fascaplysin was observed to significantly exceed that of temozolomide. Therefore, a significant feature of fascaplysin is its ability to inhibit the growth of and kill multipotent tumor cells. PMID:28356953

  2. SEROTONIN AND OTHER VASOACTIVE AGENTS IN EXPERIMENTAL DECOMPRESSION SICKNESS,

    DTIC Science & Technology

    SEROTONIN, DECOMPRESSION SICKNESS), (*VASOACTIVE AGENTS, DECOMPRESSION SICKNESS), RATS, EXERCISE(PHYSIOLOGY), DOSAGE, CHEMOTHERAPEUTIC AGENTS, BLOOD ANALYSIS, TOXICITY, BLOOD CIRCULATION, MORTALITY RATES , CANADA

  3. Effects of psoralens as anti-tumoral agents in breast cancer cells

    PubMed Central

    Panno, Maria Luisa; Giordano, Francesca

    2014-01-01

    This review examines the biological properties of coumarins, widely distributed at the highest levels in the fruit, followed by the roots, stems and leaves, by considering their beneficial effects in the prevention of some diseases and as anti-cancer agents. These compounds are well known photosensitizing drugs which have been used as pharmaceuticals for a broad number of therapeutic applications requiring cell division inhibitors. Despite this, even in the absence of ultraviolet rays they are active. The current paper mainly focuses on the effects of psoralens on human breast cancer as they are able to influence many aspects of cell behavior, such as cell growth, survival and apoptosis. In addition, analytical and pharmacological data have demonstrated that psoralens antagonize some metabolizing enzymes, affect estrogen receptor stability and counteract cell invasiveness as well as cancer drug resistance. The scientific findings summarized highlight the pleiotropic functions of phytochemical drugs, given that recently their target signals and how these are modified in the cells have been identified. The encouraging results in this field suggest that multiple modulating strategies based on coumarin drugs in combination with canonical chemotherapeutic agents or radiotherapy could be a useful approach to address the treatment of many types of cancer. PMID:25114850

  4. Heat Shock Protein translocation induced by membrane fluidization increases tumor-cell sensitivity to chemotherapeutic drugs.

    PubMed

    Dempsey, Nina C; Ireland, H Elyse; Smith, Carly M; Hoyle, Christine F; Williams, John H H

    2010-10-28

    Treatment of chronic lymphocytic leukemia (CLL) remains a challenge due to the frequency of drug resistance amongst patients. Improving the delivery of chemotherapeutic agents while reducing the expression of anti-apoptotic Heat Shock Proteins (HSPs) within the cancer cells may facilitate in overcoming this drug resistance. We demonstrate for the first time that sub-lethal doses of chemotherapeutic agents can be combined with membrane fluidizing treatments to produce a significant increase in drug efficacy and apoptosis in vitro. We show that fluidizers result in a transient decrease in intracellular HSPs, resulting in increased tumor-cell sensitivity and a membrane-associated induction of HSP gene expression.

  5. Improving chemotherapeutic efficiency in acute myeloid leukemia treatments by chemically synthesized peptide interfering with CXCR4/CXCL12 axis

    PubMed Central

    Li, Xiaojin; Guo, Hua; Duan, Hongyang; Yang, Yanlian; Meng, Jie; Liu, Jian; Wang, Chen; Xu, Haiyan

    2015-01-01

    Bone marrow stroma can protect acute myeloid leukemia (AML) cells against chemotherapeutic agents and provide anti-apoptosis and chemoresistance signals through secreting chemokine CXCL12 to activate its receptor CXCR4 on AML cells, resulting in minimal residual leukemia and relapse. Therefore disrupting the CXCR4/CXCL12 axis with antagonists is of great significance for improving chemosensitivity and decreasing relapse rate. In a previous study, we reported a novel synthetic peptide E5 with its remarkable effect on inhibiting CXCR4/CXCL12-mediated adhesion and migration of AML cells. Here we presented E5’s capacity of enhancing the therapeutic efficiency of various chemotherapeutics on AML in vitro and in vivo. Results showed that E5 can diminish bone marrow stromal cell-provided protection to leukemia cells, significantly increasing the apoptosis induced by various chemotherapeutics in multiple AML cell lines. In an AML mouse xenograft model, E5 induced 1.84-fold increase of circulating AML cells out of protective stroma niche. Combined with vincristine or cyclophosphamide, E5 inhibited infiltration of AML cells into bone marrow, liver and spleen, as well as prolonged the lifespan of AML mice compared with mice treated with chemotherapy alone. In addition, E5 presented no toxicity in vivo according to the histological analysis and routine clinical parameters of serum analysis. PMID:26538086

  6. Overseas nurses--effective therapeutic agents?

    PubMed

    Shanley, E

    1980-09-01

    Factors affecting the effectiveness of overseas people employed as psychiatric nurses are discussed. Basic cultural influences, especially different value systems between the immigrant and the host population, are seen as unlikely to be greatly altered by the environment in which the immigrant nurses find themselves. In fact a greater divergence would seem more likely to occur. The different experiences of immigrant nurses compared with nurses recruited in Britain are considered under the following headings: expectations of the immigrants on entering nursing, their contact with the host culture, the reaction of the indigenous population to the immigrant, language difficulties, and the insecurity of employment. The conclusion drawn is that the cultural differences, recruitment methods, the immigrants' experiences in employment and lack of contact with the culture of the indigenous population (apart from their deviant members) are likely to adversely affect his/her ability to function as a therapeutic agent. This is particularly important where the form of treatment is based on the social model.

  7. A New Concept of Enhancing Immuno-Chemotherapeutic Effects Against B16F10 Tumor via Systemic Administration by Taking Advantages of the Limitation of EPR Effect

    PubMed Central

    Yang, Yuting; Tai, Xiaowei; Shi, Kairong; Ruan, Shaobo; Qiu, Yue; Zhang, Zhirong; Xiang, Bing; He, Qin

    2016-01-01

    The enhanced permeability and retention (EPR) effect has been comfortably accepted, and extensively assumed as a keystone in the research on tumor-targeted drug delivery system. Due to the unsatisfied tumor-targeting efficiency of EPR effect being one conspicuous drawback, nanocarriers that merely relying on EPR effect are difficult to access the tumor tissue and consequently trigger efficient tumor therapy in clinic. In the present contribution, we break up the shackles of EPR effect on nanocarriers thanks to their universal distribution characteristic. We successfully design a paclitaxel (PTX) and alpha-galactosylceramide (αGC) co-loaded TH peptide (AGYLLGHINLHHLAHL(Aib)HHIL-Cys) -modified liposome (PTX/αGC-TH-Lip) and introduce a new concept of immuno-chemotherapy combination via accumulation of these liposomes at both spleen and tumor sites naturally and simultaneously. The PTX-initiated cytotoxicity attacks tumor cells at tumor sites, meanwhile, the αGC-triggered antitumor immune response emerges at spleen tissue. Different to the case that liposomes are loaded with sole drug, in this concept two therapeutic processes effectively reinforce each other, thereby elevating the tumor therapy efficiency significantly. The data demonstrates that the PTX/αGC-TH-Lip not only possess therapeutic effect against highly malignant B16F10 melanoma tumor, but also adjust the in vivo immune status and induce a more remarkable systemic antitumor immunity that could further suppress the growth of tumor at distant site. This work exhibits the capability of the PTX/αGC-TH-Lip in improving immune-chemotherapy against tumor after systemic administration. PMID:27698946

  8. Antibiotic and chemotherapeutic enhanced three-dimensional printer filaments and constructs for biomedical applications.

    PubMed

    Weisman, Jeffery A; Nicholson, James C; Tappa, Karthik; Jammalamadaka, UdayaBhanu; Wilson, Chester G; Mills, David K

    2015-01-01

    Three-dimensional (3D) printing and additive manufacturing holds potential for highly personalized medicine, and its introduction into clinical medicine will have many implications for patient care. This paper demonstrates the first application of 3D printing as a method for the potential sustained delivery of antibiotic and chemotherapeutic drugs from constructs for patient treatment. Our design is focused on the on-demand production of anti-infective and chemotherapeutic filaments that can be used to create discs, beads, catheters, or any medical construct using a 3D printing system. The design parameters for this project were to create a system that could be modularly loaded with bioactive agents. All 3D-printed constructs were loaded with either gentamicin or methotrexate and were optimized for efficient and extended antibacterial and cancer growth-inhibiting cytostatic activity. Preliminary results demonstrate that combining gentamicin and methotrexate with polylactic acid forms a composite possessing a superior combination of strength, versatility, and enhanced drug delivery. Antibacterial effects and a reduction in proliferation of osteosarcoma cells were observed with all constructs, attesting to the technical and clinical viability of our composites. In this study, 3D constructs were loaded with gentamicin and methotrexate, but the method can be extended to many other drugs. This method could permit clinicians to provide customized and tailored treatment that allows patient-specific treatment of disease and has significant potential for use as a tunable drug delivery system with sustained-release capacity for an array of biomedical applications.

  9. Principles and major agents in clinical oncology chemotherapy

    SciTech Connect

    Weller, R.E.

    1991-10-01

    This paper provides a brief classification of drugs available for veterinary chemotherapy, as well as justifications for their use. Some common neoplasia and the drugs of choice for their treatment are described. A listing by class of systemic chemotherapeutic agents, their mode of action, tumors responsive to the drugs, precautions and common adverse effects and mode of administration is provided. 2 tabs. (MHB)

  10. Rational Choice of Antiemetic Agents during Cancer Chemotherapy

    PubMed Central

    Brigden, Malcolm L.; Wilson, Kenneth S.; Barnett, Jeffrey B.

    1983-01-01

    Nausea and vomiting are major limitations in cancer chemotherapy. Individual susceptibility to nausea varies enormously. There is no ideal antiemetic, but some work with some chemotherapeutic agents, and some are more effective in younger patients. This article describes a flexible, stepped approach using the phenothiazines, metoclopramide, cannabinoids, anticholinergics, antihistamines and others. PMID:21283402

  11. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer

    PubMed Central

    Shree, Tanaya; Olson, Oakley C.; Elie, Benelita T.; Kester, Jemila C.; Garfall, Alfred L.; Simpson, Kenishana; Bell-McGuinn, Katherine M.; Zabor, Emily C.; Brogi, Edi; Joyce, Johanna A.

    2011-01-01

    The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response. PMID:22156207

  12. Trypanothione Reductase: A Viable Chemotherapeutic Target for Antitrypanosomal and Antileishmanial Drug Design

    PubMed Central

    Khan, M. Omar F.

    2007-01-01

    Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The process of designing selective inhibitors for the enzyme trypanothione reductase has been discussed. An overview of the different chemical classes of inhibitors of trypanothione reductase with their inhibitory activities against the parasites and their prospects as future chemotherapeutic agents are briefly revealed. PMID:21901070

  13. Developing Effective Extension Agents: Experience Concerns.

    ERIC Educational Resources Information Center

    Goddu, Roland

    This paper is a description of the requirements placed on persons selected to fill the role of extension agents for the purpose of penetrating an educational environment, installing change in an educational organization, and completing tasks as a resource outside of the education establishment. These experience concerns are summarized by…

  14. Hantzsch-Type dihydropyridines and Biginelli-type tetra-hydropyrimidines: a review of their chemotherapeutic activities.

    PubMed

    Sepehri, Saghi; Sanchez, Horacio Perez; Fassihi, Afshin

    2015-01-01

    Years after the first report on 1,4-dihydropyridines (1,4-DHPs) and 1,2,3,4-tetrahydropyrimidines (1,2,3,4-THPMs) appeared, they are revisited as plausible therapeutic agents. This is mainly due to the convenient methods that exist for their synthesis and the diverse pharmacologic properties that these scaffolds present. 1,4-Dihydropyridines and 1,2,3,4-tetrahydropyrimidines are usually regarded as analogous in several aspects. They are both prepared in multi-component reactions using very similar starting materials and synthesis protocols. This leads to common structural features between 1,4-DHPs and 1,2,3,4-THPMs, as well several related biological effects. For example, they share many pharmacological features such as analgesic, anti-tumor, antioxidant, anti-inflammatory, antitubercular, antibacterial, cardiovascular and adrenoceptor blocking activities. Numerous reviews have been devoted to the chemistry and cardiovascular effects of these compounds. However, the lack of a comprehensive literature overview on the chemotherapeutic ability of these scaffolds is behind the present attempt to provide a detailed survey of 1,4-DHPs and 1,2,3,4-THPMs and their structural features as chemotherapeutic agents.

  15. γ-Tocotrienol but not γ-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents.

    PubMed

    Kannappan, Ramaswamy; Yadav, Vivek R; Aggarwal, Bharat B

    2010-10-22

    Although γ-tocotrienol (T3), a vitamin E isolated primarily from palm and rice bran oil, has been linked with anticancer activities, the mechanism of this action is poorly understood. In this study, we investigated whether γ-T3 can modulate the STAT3 cell signaling pathway, closely linked to inflammation and tumorigenesis. We found that γ-T3 but not γ-tocopherol, the most common saturated form of vitamin E, inhibited constitutive activation of STAT3 in a dose- and time-dependent manner, and this inhibition was not cell type-specific. γ-T3 also inhibited STAT3 DNA binding. This correlated with inhibition of Src kinase and JAK1 and JAK2 kinases. Pervanadate reversed the γ-T3-induced down-regulation of STAT3 activation, suggesting the involvement of a protein-tyrosine phosphatase. When examined further, we found that γ-T3 induced the expression of the tyrosine phosphatase SHP-1, and gene silencing of the SHP-1 by small interfering RNA abolished the ability of γ-T3 to inhibit STAT3 activation, suggesting a vital role for SHP-1 in the action of γ-T3. Also γ-T3 down-modulated activation of STAT3 and induced SHP-1 in vivo. Eventually, γ-T3 down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of the cell cycle, and induction of apoptosis. This vitamin also sensitized the tumor cells to the apoptotic effects of thalidomide and bortezomib. Overall, our results suggest that γ-T3 is a novel blocker of STAT3 activation pathway both in vitro and in vivo and thus may have potential in prevention and treatment of cancers.

  16. A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs

    PubMed Central

    Gidwani, Bina; Vyas, Amber

    2015-01-01

    Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carriers, and various approaches used for the delivery. The present review article aims to assess the utility of cyclodextrin-based carriers like liposomes, niosomes, nanoparticles, micelles, millirods, and siRNA for delivery of antineoplastic agents. These systems based on cyclodextrin complexation and nanotechnology will camouflage the undesirable properties of drug and lead to synergistic or additive effect. Cyclodextrin-based nanotechnology seems to provide better therapeutic effect and sustain long life of healthy and recovered cells. Still, considerable study on delivery system and administration routes of cyclodextrin-based carriers is necessary with respect to their pharmacokinetics and toxicology to substantiate their safety and efficiency. In future, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents. PMID:26582104

  17. Learning Spanish with "Laura": The Effects of a Pedagogical Agent

    ERIC Educational Resources Information Center

    Theodoridou, Katerina

    2011-01-01

    The purpose of this study was to investigate the effects of an animated pedagogical agent on Spanish vocabulary learning. Furthermore, the study examined learners' reactions and attitudes towards the presence of the pedagogical agent in the web-based environments. A total of 47 university students enrolled in two fourth-semester Spanish classes…

  18. Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs

    PubMed Central

    Kozlowska, Anna Karolina; Topchyan, Paytsar; Kaur, Kawaljit; Tseng, Han-Ching; Teruel, Antonia; Hiraga, Toru; Jewett, Anahid

    2017-01-01

    Natural Killer (NK) cells target oral, pancreatic, lung, breast, glioblastoma and melanoma stem-like/poorly differentiated tumors. Differentiation of the abovementioned tumors with supernatants from split-anergized NK cells decreases their susceptibility to NK cells, but increases their sensitivity to cisplatin (CDDP)-mediated cell death. Breast and melanoma tumor cells with CD44 knockdown display enhanced susceptibility to NK cell-mediated lysis, potentially due to decreased differentiation. We also demonstrate that sulindac, a non-steroidal anti-inflammatory drug and a chemopreventive agent, not only limits the growth of oral tumor cells, but also aids in cancer cell elimination by NK cells. Treatment of oral tumors with sulindac, but not adriamycin inversely modulates the expression and function of NFκB and JNK, resulting in a significant down-regulation of IL-6, and VEGF secretion by oral tumor cells. In addition, increased secretion of IL-6 and VEGF is blocked by sulindac during interaction of oral tumors with NK cells. Sulindac treatment prevents synergistic induction of VEGF secretion by the tumor cells after their co-culture with untreated NK cells since non-activated NK cells lack the ability to efficiently kill tumor cells. Moreover, sulindac is able to profoundly reduce VEGF secretion by tumor cells cultured with IL-2 activated NK cells, which are able to significantly lyse the tumor cells. Based on the data presented in this study, we propose the following combinatorial approach for the treatment of stem-like/ poorly differentiated tumors in cancer patients with metastatic disease. Stem-like/ poorly differentiated tumor cells may in part undergo lysis or differentiation after NK cell immunotherapy, followed by treatment of differentiated tumors with chemotherapy and chemopreventive agents to eliminate the bulk of the tumor. This dual approach should limit tumor growth and prevent metastasis. PMID:28367234

  19. Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

    NASA Astrophysics Data System (ADS)

    Huber, S. E.; Śmiałek, M. A.; Tanzer, K.; Denifl, S.

    2016-06-01

    Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO-, water, and the amidogen (NH2) radical. The second and third most dominant dissociation channels are associated with formation of NCNH- and NHCONH2-, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH2-/O-, OH-, CN-, HNOH-, NCONH2-, and ONHCONH2-.

  20. [Experience with vaginal suppositories containing chemotherapeutic agents (author's transl)].

    PubMed

    Török, J; Kószó, E; Altmayer, P; Mezey, G

    1981-01-01

    The authors determined the release of chloramphenicol, oxytetracycline, neomycin and sulphadimidine from different bases (polyoxethene mass, solid fat, 95% solid fat +5% Span 20). The diffusion of chloramphenicol and sulphadimidine was best from hydrophilic bases; that of oxytetracycline and neomycin, from emulsifier-containing lipophil bases. This may be explained by the solubilities of the pharmaca and by interactions between base and active substance.

  1. Synthesis of Taxol-Like Prostate Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2006-11-01

    opening reaction of sulfolene 1 where the corresponding chiral epoxide 19 was readily available from L-tartaric acid.5) The resulting secondary alcohol...toluene, reflux OH OTBS 41% over 2 steps MOMBr DIPEA, DMAP DCMSO2 + OMOM OTBS 64% 1) TBAF 2) SO3- pyridine OMOM O 20191 21 22 40% over 2 steps

  2. Design and Sythesis of New Breast Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2000-08-01

    Point, PA) Smith, Kline and Beckmann Invited Lecturer, Symposium on Organic Synthesis , Great Lakes Regional ACS Meeting, Dekalb, Illinois Invited...Ann Arbor, Michigan Invited Lecturer, Symposium on Organic Synthesis , Middle Atlantic Regional ACS Meeting, Baltimore, Maryland Technion-Israel...Photochemical Key Steps in Organic Synthesis 1994, J. Mattay and A. Griesbeck, Eds., VCH, Weinheim, 109-111. 40. K. Davis, T. Berrodin, T., J. Stelmach

  3. Mechanisms of tumour resistance against chemotherapeutic agents in veterinary oncology.

    PubMed

    Klopfleisch, R; Kohn, B; Gruber, A D

    2016-01-01

    Several classes of chemotherapy drugs are used as first line or adjuvant treatment of the majority of tumour types in veterinary oncology. However, some types of tumour are intrinsically resistant to several anti-cancer drugs, and others, while initially sensitive, acquire resistance during treatment. Chemotherapy often significantly prolongs survival or disease free interval, but is not curative. The exact mechanisms behind intrinsic and acquired chemotherapy resistance are unknown for most animal tumours, but there is increasing knowledge on the mechanisms of drug resistance in humans and a few reports on molecular changes in resistant canine tumours have emerged. In addition, approaches to overcome or prevent chemotherapy resistance are becoming available in humans and, given the overlaps in molecular alterations between human and animal tumours, these may also be relevant in veterinary oncology. This review provides an overview of the current state of research on general chemotherapy resistance mechanisms, including drug efflux, DNA repair, apoptosis evasion and tumour stem cells. The known resistance mechanisms in animal tumours and the potential of these findings for improving treatment efficacy in veterinary oncology are also explored.

  4. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  5. Antidotal Effects of Curcumin Against Agents-Induced Cardiovascular Toxicity.

    PubMed

    Farkhondeh, Tahereh; Samarghandian, Saeed

    Curcumin, the major phenolic compound in turmeric, shows preventive effects in various diseases. Curcumin is commonly found in rhizome of the Curcuma species and traditionally used in herbal medicine. Numeros studies has indicated that curcumin posses protective effects against toxic agents in various systems including cardiovascular. This study found that curcumin may be effective in cardiovascular diseases induced by toxic agents including Streptozotocin, Doxorubicin, Cyclosporin A, Methotrexate, Isoproterenol, Cadmium, Diesel exhaust particle, Nicotine, Hydrogen peroxide, and tert- Butyl hydroperoxide. However, due to the lake of information on human, further studies are needed to determine the efficacy of curcumin as an antidote agent. The present study aimed to critically review the recent literature data from that regarding the protective effects of curcumin against agents-induced cardiovascular toxicity.

  6. Research to Identify Effective Antifungal Agents, 1993 Annual Report.

    SciTech Connect

    Schreck, Carl

    1993-10-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990, 1991, and 1992). The objectives of the present study were to select and evaluate candidate fungicides.

  7. Research to Identify Effective Antifungal Agents, 1991 Annual Report.

    SciTech Connect

    Schreck, Carl

    1991-09-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990). The objectives of the present study was to evaluate up to 10 candidate fungicides.

  8. Effects of a Pedagogical Agent's Emotional Expressiveness on Learner Perceptions

    NASA Technical Reports Server (NTRS)

    Romero, Enilda J.; Watson, Ginger S.

    2012-01-01

    The use of animated pedagogical agents or avatars in instruction has lagged behind their use in entertainment. This is due in part to the cost and complexity of development and implementation of agents in educational settings, but also results from a lack of research to understand how emotions from animated agents influence instructional effectiveness. The phenomenological study presented here assesses the perceptions of eight learners interacting with low and high intensity emotionally expressive pedagogical agents in a computer-mediated environment. Research methods include maximum variation and snowball sampling with random assignment to treatment. The resulting themes incorporate perceptions of importance, agent humanness, enjoyment, implementation barriers, and suggested improvements. Design recommendations and implications for future research are presented.

  9. Multiphysics and Multiscale Analysis for Chemotherapeutic Drug

    PubMed Central

    Zhang, Linan; Kim, Sung Youb; Kim, Dongchoul

    2015-01-01

    This paper presents a three-dimensional dynamic model for the chemotherapy design based on a multiphysics and multiscale approach. The model incorporates cancer cells, matrix degrading enzymes (MDEs) secreted by cancer cells, degrading extracellular matrix (ECM), and chemotherapeutic drug. Multiple mechanisms related to each component possible in chemotherapy are systematically integrated for high reliability of computational analysis of chemotherapy. Moreover, the fidelity of the estimated efficacy of chemotherapy is enhanced by atomic information associated with the diffusion characteristics of chemotherapeutic drug, which is obtained from atomic simulations. With the developed model, the invasion process of cancer cells in chemotherapy treatment is quantitatively investigated. The performed simulations suggest a substantial potential of the presented model for a reliable design technology of chemotherapy treatment. PMID:26491672

  10. Cardiotoxicity of Molecularly Targeted Agents

    PubMed Central

    Hedhli, Nadia; Russell, Kerry S

    2011-01-01

    Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics. PMID:22758623

  11. Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

    PubMed

    Tsen, Andrew R; Long, Patrick M; Driscoll, Heather E; Davies, Matthew T; Teasdale, Benjamin A; Penar, Paul L; Pendlebury, William W; Spees, Jeffrey L; Lawler, Sean E; Viapiano, Mariano S; Jaworski, Diane M

    2014-03-15

    Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors.

  12. Inhibitory effects of antimicrobial agents against Fusarium species.

    PubMed

    Kawakami, Hideaki; Inuzuka, Hiroko; Hori, Nobuhide; Takahashi, Nobumichi; Ishida, Kyoko; Mochizuki, Kiyofumi; Ohkusu, Kiyofumi; Muraosa, Yasunori; Watanabe, Akira; Kamei, Katsuhiko

    2015-08-01

    We investigated the inhibitory effects of antibacterial, biocidal, and antifungal agents against Fusarium spp. Seven Fusarium spp: four F. falciforme (Fusarium solani species complex), one Fusarium spp, one Fusarium spp. (Fusarium incarnatum-equiseti species complex), and one F. napiforme (Gibberella fujikuroi species complex), isolated from eyes with fungal keratitis were used in this study. Their susceptibility to antibacterial agents: flomoxef, imipenem, gatifloxacin, levofloxacin, moxifloxacin, gentamicin, tobramycin, and Tobracin® (contained 3,000 μg/ml of tobramycin and 25 μg/ml of benzalkonium chloride (BAK), a biocidal agent: BAK, and antifungal agents: amphotericin B, pimaricin (natamycin), fluconazole, itraconazole, miconazole, voriconazole, and micafungin, was determined by broth microdilution tests. The half-maximal inhibitory concentration (IC50), 100% inhibitory concentration (IC100), and minimum inhibitory concentration (MIC) against the Fusarium isolates were determined. BAK had the highest activity against the Fusarium spp. except for the antifungal agents. Three fluoroquinolones and two aminoglycosides had inhibitory effects against the Fusarium spp. at relatively high concentrations. Tobracin® had a higher inhibitory effect against Fusarium spp. than tobramycin alone. Amphotericin B had the highest inhibitory effect against the Fusarium spp, although it had different degrees of activity against each isolate. Our findings showed that fluoroquinolones, aminoglycosides, and BAK had some degree of inhibitory effect against the seven Fusarium isolates, although these agents had considerably lower effect than amphotericin B. However, the inhibitory effects of amphotericin B against the Fusarium spp. varied for the different isolates. Further studies for more effective medications against Fusarium, such as different combinations of antibacterial, biocidal, and antifungal agents are needed.

  13. Effects of Sterilizing Agents on Microorganisms

    DTIC Science & Technology

    1963-03-01

    light increases with the incubation of Escherichia coli at 15, but the rate of in- 85. ESTUDIO DE LOS EFECTOS QUE PRODUCE duction of mutations...between the deoxyribonucleic acid content of a cell and its response to irradiation: 5-fluor- 86. ESTUDIO DE LOS EFECTOS QUE PRODUCE ouracil treated...EFFECTS OF ULTRAVIOLET LIGHT ON 84. ESTUDIO DE LOS EFECTOS QUE PRODUCE BACTERIA. III. ALTERATIONS IN THE LA LUZ ULTRAVIOLETA SOBRE LAS PHYSIOLOGICAL

  14. Small-molecule inhibitors of proteins involved in base excision repair potentiate the anti-tumorigenic effect of existing chemotherapeutics and irradiation

    PubMed Central

    Reed, April M; Fishel, Melissa L; Kelley, Mark R

    2009-01-01

    There has been a recent upsurge in the development of small-molecule inhibitors specific to DNA repair proteins or proteins peripherally involved in base excision repair and the DNA damage response. These specific, nominally toxic inhibitors are able to potentiate the effect of existing cancer cell treatments in a wide array of cancers. One of the largest obstacles to overcome in the treatment of cancer is incomplete killing with initial cancer treatments, leading to resistant cancer. The progression of our understanding of cancer and normal cell responses to DNA damage has allowed us to develop biomarkers that we can use to help us predict responses of cancers, more specifically target cancer cells and overcome resistance. Initial successes using these small-molecule DNA repair inhibitors in target-validation experiments and in the early stages of clinical trials indicate an important role for these inhibitors, and allow for the possibility of a future in which cancers are potentially treated in a highly specific, individual manner. PMID:19519210

  15. [Development of quality of life (QOL) questionnaire for use of lung cancer patients in palliative therapy--study of validity and reliability no. 2, the effects of chemotherapeutics in QOL].

    PubMed

    Ishihara, Y; Sakai, H; Nukariya, N; Kobayashi, K; Yoneda, S; Matsuoka, R; Hojou, N; Nishiwaki, Y; Hoshi, A; Kuratomi, Y

    1995-07-01

    The effects of cisplatin and carboplatin in QOL were studied using a QOL questionnaire seeking to conform their validity and reliability in lung cancer patients. The questionnaire was composed of eleven items; appetite, feeling, sleep, mental fatigue, pain, anxiety, daily activity, abdominal and respiratory conditions, linear analog and face scale as global scale. The data were collected from 21 patients treated with cisplatin (Cis group) and 9 patients administered carboplatin (Carbo group). Chronological changes of QOL were measured by AUC (area under the curve) method. 1) The total score of 9 items, linear analog and face scales rose immediately to the highest levels (worse) after treatment and maintained this level for 1 week in the Cis group. The Carbo group levels rose from 3 days and returned to the control level at 9 days after treatment. 2) AUC of the total score, linear analog and face scales in the Cis group increased significantly when compared with those of the Carbo group. 3) When compared with the Cis and Carbo groups the physiological and active scales were not different, but the psychological scale showed a significant difference between the two groups. 4) The total score of the psychological scale correlated the abdominal score in the Cis group, but not in the Carbo group. 5) Sleep and mental fatigue were related to the aggravation of QOL at 5-6 days after Carboplatin treatment. These results suggested that this QOL questionnaire had sufficient sensitivity to reflect any chemotherapeutic side-effects. 6) AUC is useful method in chronological evaluation of QOL.

  16. Role of pregnane X receptor in chemotherapeutic treatment

    PubMed Central

    Zhuo, Wei; Hu, Lei; Lv, Jinfeng; Wang, Hongbing; Zhou, Honghao; Fan, Lan

    2015-01-01

    Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that differently expresses not only in human normal tissues but also in numerous types of human cancers. PXR can be activated by many endogenous substances and exogenous chemicals, and thus affects chemotherapeutic effects and intervenes drug–drug interactions by regulating its target genes involving drug metabolism and transportation, cell proliferation and apoptosis, and modulating endobiotic homeostasis. Tissue and context-specific regulation of PXR contributes to diverse effects in the treatment for numerous cancers. Genetic variants of PXR lead to intra- and inter-individual differences in the expression and inducibility of PXR, resulting in different responses to chemotherapy in PXR-positive cancers. The purpose of this review is to summarize and discuss the role of PXR in the metabolism and clearance of anticancer drugs. It is also expected that this review will provide insights into PXR-mediated enhancement for chemotherapeutic treatment, prediction of drug–drug interactions and personalized medicine. PMID:24889719

  17. Research to Identify Effective Antifungal Agents, 1992 Annual Report.

    SciTech Connect

    Schreck, Carl

    1993-03-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990 and Schreck et al. 1991). The objectives of the present study were to select and evaluate up to 10 candidate fungicides.

  18. Efficacy of oncolytic herpesvirus NV1020 can be enhanced by combination with chemotherapeutics in colon carcinoma cells.

    PubMed

    Gutermann, Anja; Mayer, Elfriede; von Dehn-Rothfelser, Karin; Breidenstein, Claudia; Weber, Mihaela; Muench, Martina; Gungor, Denis; Suehnel, Juergen; Moebius, Ulrich; Lechmann, Martin

    2006-12-01

    NV1020, an oncolytic herpes simplex virus type 1, can destroy colon cancer cells by selectively replicating within these cells, while sparing normal cells. NV1020 is currently under investigation in a clinical phase I/II trial as an agent for the treatment of colon cancer liver metastases, in combination with conventional chemotherapeutic agents such as 5-fluorouracil (5-FU), SN38 (the active metabolite of irinotecan), and oxaliplatin. To study the synergy of NV1020 and chemotherapy, cytotoxicity and viral replication were evaluated in vitro by treating various human and murine colon carcinoma cell lines, using a colorimetric viability assay, a clonogenic assay, and a plaque-forming assay. In vivo experiments, using a subcutaneous syngeneic CT-26 tumor model in BALB/c mice, were performed to determine the efficacy of combination therapy. In vitro studies showed that the efficacy of NV1020 on human colon carcinoma cell lines HT-29, WiDr, and HCT-116 was additively or synergistically enhanced in combination with 5-FU, SN38, or oxaliplatin. The sequence of application was not important and effects were still apparent after a 21-day incubation period. Three intra-tumoral treatments with NV1020 (1 x 10(7) plaque-forming units), followed by three subcutaneous treatments with 5-FU (50 mg/kg), resulted in substantially higher inhibition of tumor growth and prolongation of survival compared with monotherapies (NV1020/5-FU vs. NV1020, p = 0.027). On WiDr cells, reduced replication of NV1020, in combination with 5-FU, indicated that additive and synergistic effects of combination therapy must be independent from viral replication. These results suggest that NV1020, in combination with chemotherapy, is a promising therapy for treating patients with metastatic colorectal cancer of the liver. We hypothesize that infection of cells with NV1020 sensitizes the infected cells for the cytotoxic effect of the chemotherapeutics.

  19. Effects of Anesthetic Agent Propofol on Postoperative Sex Hormone Levels

    PubMed Central

    Kim, H.; Ku, S.-Y.; Kim, H. C.; Suh, C. S.; Kim, S. H.; Choi, Y. M.

    2016-01-01

    Introduction: Several studies have found anesthetic agents including propofol in ovarian follicular fluid. However, little is known about the effect of anesthetic agents on ovarian function. We aimed to investigate whether there were differences in the postoperative levels of sex hormones when propofol was used as the anesthetic agent. Methods: A retrospective review was done of 80 patients who underwent ovarian surgery, with 72 infertile women serving as controls. Patients were included in the study if their serum estradiol (E2) and follicle stimulating hormone (FSH) levels were measured during their first postoperative menstrual cycle. Results: Patients were grouped according to the use or non-use of propofol as follows: propofol group (n = 39) and non-propofol group (n = 41). The control group did not undergo surgery. Postoperative E2 levels did not differ between the three groups, but FSH levels were significantly higher in the patients who had undergone surgery compared to controls (p < 0.05). Post-hoc analysis of E2 and FSH levels in the propofol and non-propofol groups did not show any significant differences. Conclusions: The use of propofol did not result in any differences compared to other anesthetic agents in terms of postoperative sex hormone levels after gynecologic surgery. The type of anesthetic agent does not seem to affect the postoperative levels of female sex hormones. PMID:27134297

  20. Effects of bleaching agents on surface roughness of filling materials.

    PubMed

    Markovic, Ljubisa; Jordan, Rainer Andreas; Glasser, Marie-Claire; Arnold, Wolfgang Hermann; Nebel, Jan; Tillmann, Wolfgang; Ostermann, Thomas; Zimmer, Stefan

    2014-01-01

    The aim of this study was to use a non-tactile optical measurement system to assess the effects of three bleaching agents' concentrations on the surface roughness of dental restoration materials. Two composites (Grandio, Venus) and one glass ionomer cement (Ketac Fil Plus) were used in this in vitro study. Specimens were treated with three different bleaching agents (16% and 22% carbamide peroxide (Polanight) and 38% hydrogen peroxide (Opalescence Boost)). Surface roughness was measured with an optical profilometer (Infinite Focus G3) before and after the bleaching treatment. Surface roughness increased in all tested specimens after bleaching treatment (p<0.05). Our in vitro study showed that dental bleaching agents influenced the surface roughness of different restoration materials, and the restoration material itself was shown to have an impact on alteration susceptibility. There seemed to be no clinical relevance in case of an optimal finish.

  1. Chemotherapeutic trial to control enterobiasis in schoolchildren.

    PubMed

    Yang, Y S; Kim, S W; Jung, S H; Huh, S; Lee, J H

    1997-12-01

    To assess several chemotherapeutic schemes for control of enterobiasis, 738 children in five primary schools in Chunchon, Korea, were studied from May 1994 to June 1995. They were divided into 6 groups by the schemes: treatment of once or twice a year; treatment of positive cases or of whole class students; treatment with or without family members. The overall egg positive rate before intervention was 17.5% out of 789 children. Treating all individuals in a class together with family members of positive cases brought better control efficacy than other schemes (p = 0.000). However, when egg positive rate is less than 30%, treating only egg positive cases also can reduce egg positive rate. The confounding factors for the enterobiasis control in primary schoolchildren were new-comer to a class and familial infection.

  2. The neurotrophic and neuroprotective effects of psychotropic agents

    PubMed Central

    Hunsberger, Joshua; Austin, Daniel R.; Henter, Ioline D.; Chen, Guang

    2009-01-01

    Accumulating evidence suggests that psychotropic agents such as mood stabilizers, antidepressants, and antipsychotics realize their neurotrophic/neuroprotective effects by activating the mitogen activated protein kinaselextracellular signal-related kinase, PI3-kinase, and winglesslglycogen synthase kinase (GSK) 3 signaling pathways. These agents also upregulate the expression of trophic/protective molecules such as brain-derived neurotrophic factor, nerve growth factor, B-cell lymphoma 2, serine-threonine kinase, and Bcl-2 associated athanogene 1, and inactivate proapoptotic molecules such as GSK-3, They also promote neurogenesis and are protective in models of neurodegenerative diseases and ischemia. Most if not all, of this evidence was collected from animal studies that used clinically relevant treatment regimens. Furthermore, human imaging studies have found that these agents increase the volume and density of brain tissue, as well as levels of N-acetyl aspartate and glutamate in selected brain regions. Taken together, these data suggest that the neurotrophic/neuroprotective effects of these agents have broad therapeutic potential in the treatment, not only of mood disorders and schizophrenia, but also neurodegenerative diseases and ischemia. PMID:19877500

  3. [Neurophysiological analysis of the effects of antihypoxic versus psychotropic agents].

    PubMed

    Krapivin, S V; Malyshev, A Iu; Kharitonov, A V; Ermishina, O S; Shubin, S N; Luk'ianova, L D

    2002-01-01

    The Fourie EEG spectral analysis of thr sensomotor cortex and dorsal hypocampus in freely moving rats could reveal the common pharmacological EEG effects of different antihypoxic agents (gutimin, amtizole, emoxipine, and 3-OPK). All the agents decreased the total EEG power (they all reduced the absolute power in all frequency bands) and simultaneously enhanced (2 relative power. The former suggests that there was a decrease in the energetic level of bioelectric fluctuations, which may indicate that the brain reduces its energetic functioning level. The latter means that antihypoxic drugs activate the central nervous system. This effect may normalize EEG activity during hypoxic conditions, which causes the enhancement of slow-wave activity and reduces fast EEG activity. The pharmacological EEG effects of different groups of psychotropic drugs (nootropic drugs, psychostimulants, antidepressants, benzodiazepine tranquilizers, etc.) versus antihypoxants are discussed.

  4. Can immunostimulatory agents enhance the abscopal effect of radiotherapy?

    PubMed

    Levy, Antonin; Chargari, Cyrus; Marabelle, Aurelien; Perfettini, Jean-Luc; Magné, Nicolas; Deutsch, Eric

    2016-07-01

    Ionising radiation (IR) may harm cancer cells through a rare indirect out-of-field phenomenon described as the abscopal effect. Increasing evidence demonstrates that radiotherapy could be capable of generating tumour-specific immune responses. On the other hand, effects of IR also include inhibitory immune signals on the tumour microenvironment. Following these observations, and in the context of newly available immunostimulatory agents in metastatic cancers (anti-cytotoxic T lymphocyte-associated antigen 4 and programmed cell death protein-1 or -ligand 1 [PD1 or PDL-1]), there is a remarkable potential for synergistic combinations of IR with such agents that act through the reactivation of immune surveillance. Here, we present and discuss the pre-clinical and clinical rationale supporting the enhancement of the abscopal effect of IR on the blockade of immune checkpoints and discuss the evolving potential of immunoradiotherapy.

  5. Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4

    PubMed Central

    Chang, Bo Yoon; Kim, Seon Beom; Lee, Mi Kyeong; Park, Hyun; Kim, Sung Yeon

    2015-01-01

    Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent. PMID:26473845

  6. Effects of quaternary ammonium chain length on antibacterial bonding agents.

    PubMed

    Li, F; Weir, M D; Xu, H H K

    2013-10-01

    The objectives of this study were to synthesize new quaternary ammonium methacrylates (QAMs) with systematically varied alkyl chain lengths (CL) and to investigate, for the first time, the CL effects on antibacterial efficacy, cytotoxicity, and dentin bond strength of bonding agents. QAMs were synthesized with CL of 3 to 18 and incorporated into Scotchbond Multi-Purpose (SBMP) bonding agent. The cured resins were inoculated with Streptococcus mutans. Bacterial early attachment was investigated at 4 hrs. Biofilm colony-forming units (CFU) were measured after 2 days. With CL increasing from 3 to 16, the minimum inhibitory concentration and minimum bactericidal concentration were decreased by 5 orders of magnitude. Incorporating QAMs into SBMP reduced bacterial early attachment, with the least colonization at CL = 16. Biofilm CFU for CL = 16 was 4 log lower than SBMP control (p < .05). All groups had similar dentin bond strengths (p > .1). The new antibacterial materials had fibroblast/odontoblast viability similar to that of commercial controls. In conclusion, increasing the chain length of new QAMs in bonding agents greatly increased the antibacterial efficacy. A reduction in Streptococcus mutans biofilm CFU by 4 log could be achieved, without compromising bond strength and cytotoxicity. New QAM-containing bonding agents are promising for a wide range of restorations to inhibit biofilms.

  7. Effects of Quaternary Ammonium Chain Length on Antibacterial Bonding Agents

    PubMed Central

    Li, F.; Weir, M.D.; Xu, H.H.K.

    2013-01-01

    The objectives of this study were to synthesize new quaternary ammonium methacrylates (QAMs) with systematically varied alkyl chain lengths (CL) and to investigate, for the first time, the CL effects on antibacterial efficacy, cytotoxicity, and dentin bond strength of bonding agents. QAMs were synthesized with CL of 3 to 18 and incorporated into Scotchbond Multi-Purpose (SBMP) bonding agent. The cured resins were inoculated with Streptococcus mutans. Bacterial early attachment was investigated at 4 hrs. Biofilm colony-forming units (CFU) were measured after 2 days. With CL increasing from 3 to 16, the minimum inhibitory concentration and minimum bactericidal concentration were decreased by 5 orders of magnitude. Incorporating QAMs into SBMP reduced bacterial early attachment, with the least colonization at CL = 16. Biofilm CFU for CL = 16 was 4 log lower than SBMP control (p < .05). All groups had similar dentin bond strengths (p > .1). The new antibacterial materials had fibroblast/odontoblast viability similar to that of commercial controls. In conclusion, increasing the chain length of new QAMs in bonding agents greatly increased the antibacterial efficacy. A reduction in Streptococcus mutans biofilm CFU by 4 log could be achieved, without compromising bond strength and cytotoxicity. New QAM-containing bonding agents are promising for a wide range of restorations to inhibit biofilms. PMID:23958761

  8. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy

    PubMed Central

    Tamburrino, Anna; Piro, Geny; Carbone, Carmine; Tortora, Giampaolo; Melisi, Davide

    2013-01-01

    Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients’ survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype. PMID:23641216

  9. Ubiquitin E3 ligase CRL4(CDT2/DCAF2) as a potential chemotherapeutic target for ovarian surface epithelial cancer.

    PubMed

    Pan, Wei-Wei; Zhou, Jian-Jie; Yu, Chao; Xu, Ying; Guo, Lian-Jun; Zhang, Hai-Yi; Zhou, Dawang; Song, Fang-Zhou; Fan, Heng-Yu

    2013-10-11

    Cullin-RING ubiquitin ligases (CRLs) are the largest family of E3 ligases and require cullin neddylation for their activation. The NEDD8-activating enzyme inhibitor MLN4924 reportedly blocked cullin neddylation and inactivated CRLs, which resulted in apoptosis induction and tumor suppression. However, CRL roles in ovarian cancer cell survival and the ovarian tumor repressing effects of MLN4924 are unknown. We show here that CRL4 components are highly expressed in human epithelial ovarian cancer tissues. MLN4924-induced DNA damage, cell cycle arrest, and apoptosis in ovarian cancer cells in a time- and dose-dependent manner. In addition, MLN4924 sensitized ovarian cancer cells to other chemotherapeutic drug treatments. Depletion of CRL4 components Roc1/2, Cul4a, and DDB1 had inhibitory effects on ovarian cancer cells similar to MLN4924 treatment, which suggested that CRL4 inhibition contributed to the chemotherapeutic effect of MLN4924 in ovarian cancers. We also investigated for key CRL4 substrate adaptors required for ovarian cancer cells. Depleting Vprbp/Dcaf1 did not significantly affect ovarian cancer cell growth, even though it was expressed by ovarian cancer tissues. However, depleting Cdt2/Dcaf2 mimicked the pharmacological effects of MLN4924 and caused the accumulation of its substrate, CDT1, both in vitro and in vivo. MLN4924-induced DNA damage and apoptosis were partially rescued by Cdt1 depletion, suggesting that CRL4(CDT2) repression and CDT1 accumulation were key biochemical events contributing to the genotoxic effects of MLN4924 in ovarian cancer cells. Taken together, these results indicate that CRL4(CDT2) is a potential drug target in ovarian cancers and that MLN4924 may be an effective anticancer agent for targeted ovarian cancer therapy.

  10. The involvement of hypoxia-inducible factor-1alpha in the susceptibility to gamma-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells.

    PubMed

    Sasabe, Eri; Zhou, Xuan; Li, Dechao; Oku, Naohisa; Yamamoto, Tetsuya; Osaki, Tokio

    2007-01-15

    The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) is the key regulator that controls the hypoxic response of mammalian cells. The overexpression of HIF-1alpha has been demonstrated in many human tumors. However, the role of HIF-1alpha in the therapeutic efficacy of chemotherapy and radiotherapy in cancer cells is poorly understood. In this study, we investigated the influence of HIF-1alpha expression on the susceptibility of oral squamous cell carcinoma (OSCC) cells to chemotherapeutic drugs (cis-diamminedichloroplatinum and 5-fluorouracil) and gamma-rays. Treatment with chemotherapeutic drugs and gamma-rays enhanced the expression and nuclear translocation of HIF-1alpha, and the susceptibility of OSCC cells to the drugs and gamma-rays was negatively correlated with the expression level of HIF-1alpha protein. The overexpression of HIF-1alpha induced OSCC cells to become more resistant to the anticancer agents, and down-regulation of HIF-1alpha expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1alpha-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were downregulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that enhanced HIF-1alpha expression is related to the resistance of tumor cells to chemo- and radio-therapy and that HIF-1alpha is an effective therapeutic target for cancer treatment.

  11. The effect of alkaline agents on retention of EOR chemicals

    SciTech Connect

    Lorenz, P.B.

    1991-07-01

    This report summarizes a literature survey on how alkaline agents reduce losses of surfactants and polymers in oil recovery by chemical injection. Data are reviewed for crude sulfonates, clean anionic surfactants, nonionic surfactants, and anionic and nonionic polymers. The role of mineral chemistry is briefly described. Specific effects of various alkaline anions are discussed. Investigations needed to improve the design of alkaline-surfactant-polymer floods are suggested. 62 refs., 28 figs., 6 tabs.

  12. Combination of metformin with chemotherapeutic drugs via different molecular mechanisms.

    PubMed

    Peng, Mei; Darko, Kwame Oteng; Tao, Ting; Huang, Yanjun; Su, Qiongli; He, Caimei; Yin, Tao; Liu, Zhaoqian; Yang, Xiaoping

    2017-03-01

    Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits. Interestingly, metformin experiences a diversity of molecular mechanisms when it combines different chemotherapeutic drugs. For example, AMPK/mTOR signaling pathway activation plays a major role when it combines with hormone modulating drugs. In contrast, suppression of HIF-1, p-gp and MRP1 protein expression is its main mechanism when metformin combines with anti-metabolites. Furthermore, when combining of metformin with antibiotics, inhibition of oxidative stress and inflammatory signaling pathway becomes a novel pharmaceutical mechanism for its cardio-protective effect. Induction of apoptotic mitochondria and nucleus could be the major player for the synergistic effect of its combination with cisplatin. In contrast, down-regulation of lipoprotein or cholesterol synthesis might be the undefined molecular base when metformin combines with taxane. Thus, deep exploration of molecular mechanisms of metformin with these different drugs is critical to understand its synergistic effect and help for personalized administration. In this mini-review, detailed molecular mechanisms of these combinations are discussed and summarized. This work will promote better understanding of molecular mechanisms of metformin and provide precise targets to identify specific patient groups to achieve satisfactory treatment efficacy.

  13. Effect of bleaching agent on dental ceramics roughness.

    PubMed

    Vanderlei, Aleska D; Passos, Sheila P; Salazar-Marocho, Susana M; Pereira, Sarina Mb; Vásquez, Vanessa Zc; Bottino, Marco A

    2010-01-01

    The aim of this study was to assess the effect of bleaching agents (10% and 16% carbamide peroxide) on the roughness of two dental ceramics in vitro, and to analyze the surface by scanning electronic microscopy (SEM). Two bleaching agents (10% and 16%/Whiteness, FGM Gel) and two microparticle feldspathic ceramics (Vita VM7 and Vita VM13) were used. Forty disks of Vita VM7 and Vita VM13 ceramic were manufactured, measuring 4 mm in diameter and 4 mm high, in accordance with the manufacturers' recommendations, and were divided into 4 groups (n = 10): (1) VM7 + Whiteness 10%; (2) VM7 + Whiteness 16%; (3) VM13 + Whiteness 10%; (4) VM13 + Whiteness 16%. The bleaching agent was applied for 8 hours a day for 15 days and during the intervals the test specimens were stored in distilled water at 37 degrees C. The roughness (Ra) of the test specimens was evaluated before and after exposure to the bleaching agents using a laser roughness meter and the topographic description was analyzed by SEM. The statistical analysis of roughness data showed significant differences in the VM7 groups, using paired t-test, p = 0.05 (VM7 + Whiteness 10%: p = 0.002; VM7 + Whiteness 16%: p = 0.001) and two-sample t-test (VM7 p = 0.047), and no significant difference was found among VM13 groups. The qualitative SEM analysis showed different degrees of surface changes. The results suggest that the roughness of the tested ceramic surfaces increased after exposure to the bleaching agents.

  14. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.

    PubMed

    Munson, Jennifer M; Fried, Levi; Rowson, Sydney A; Bonner, Michael Y; Karumbaiah, Lohitash; Diaz, Begoña; Courtneidge, Sara A; Knaus, Ulla G; Brat, Daniel J; Arbiser, Jack L; Bellamkonda, Ravi V

    2012-03-28

    The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB-mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.

  15. Parasite prolyl oligopeptidases and the challenge of designing chemotherapeuticals for Chagas disease, leishmaniasis and African trypanosomiasis.

    PubMed

    Bastos, I M D; Motta, F N; Grellier, P; Santana, J M

    2013-01-01

    The trypanosomatids Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp. cause Chagas disease, leishmaniasis and human African trypanosomiasis, respectively. It is estimated that over 10 million people worldwide suffer from these neglected diseases, posing enormous social and economic problems in endemic areas. There are no vaccines to prevent these infections and chemotherapies are not adequate. This picture indicates that new chemotherapeutic agents must be developed to treat these illnesses. For this purpose, understanding the biology of the pathogenic trypanosomatid- host cell interface is fundamental for molecular and functional characterization of virulence factors that may be used as targets for the development of inhibitors to be used for effective chemotherapy. In this context, it is well known that proteases have crucial functions for both metabolism and infectivity of pathogens and are thus potential drug targets. In this regard, prolyl oligopeptidase and oligopeptidase B, both members of the S9 serine protease family, have been shown to play important roles in the interactions of pathogenic protozoa with their mammalian hosts and may thus be considered targets for drug design. This review aims to discuss structural and functional properties of these intriguing enzymes and their potential as targets for the development of drugs against Chagas disease, leishmaniasis and African trypanosomiasis.

  16. Effective Coordination of Multiple Intelligent Agents for Command and Control

    DTIC Science & Technology

    2003-09-01

    Multi - Agent System (MAS) in which heterogeneous agents engage in relations with the support of distributed infrastructure services. The goal of RETSINA project has been to provide the necessary infrastructure and agent types to allow an open system of agents whose interactions are facilitated rather than managed by infrastructure components. Another goal has been to create autonomous software agents functioning robustly in distributed environments, agents that are reusable in different application contexts, and that respond intelligently to changes in their

  17. The effects of thermally reversible agents on PVC stability properties

    NASA Astrophysics Data System (ADS)

    Wang, J.; Yao, J.; Xiong, X. H.; Jia, C. X.; Ren, R.; Chen, P.; Liu, X. M.

    2016-07-01

    One kind of thermally reversible cross-linking agents for improving PVC thermally stability was synthesized. The chemical structure and thermally reversible characteristics of cross-linking agents were investigated by FTIR and DSC analysis, respectively. FTIR results confirmed that the cyclopentadienyl barium mercaptides ((CPD-C2H4S)2Ba) were successfully synthesized. DSC results showed it has thermally reversible characteristics and the depolymerization temperature was between 170 °C and 205 °C. The effects of cross-linking reaction time on gel content of Poly(vinyl chloride) compounds was evaluated. The gel content value arrived at 42% after being cross-linked for 25 min at 180 C. The static thermally stability measurement proved that the thermally stability of PVC compounds was improved.

  18. Bacteriocins as Potential Anticancer Agents

    PubMed Central

    Kaur, Sumanpreet; Kaur, Sukhraj

    2015-01-01

    Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have non-specific toxicity toward normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeutic potential of bacteriocins against various types of cancer cell lines. Bacteriocins are ribosomally-synthesized cationic peptides secreted by almost all groups of bacteria. Some bacteriocins have shown selective cytotoxicity toward cancer cells as compared to normal cells. This makes them promising candidates for further investigation and clinical trials. In this review article, we present the overview of the various cancer cell-specific cytotoxic bacteriocins, their mode of action and efficacies. PMID:26617524

  19. Nonhemostatic adverse effects of anticoagulants and antiplatelet agents.

    PubMed

    Walenga, Jeanine M; Thethi, Indermohan; Lewis, Bruce E

    2012-11-01

    The topic of adverse effects of drugs is now receiving due attention in both the lay and medical communities. For drugs of the coagulation disorder class, such as anticoagulants and antiplatelet agents, the obvious adverse effects are bleeding from a dose too high and thrombosis from a dose too low. However, these drugs have other potential adverse effects that are not directly related to blood coagulation, yet cannot be dismissed due to their medical importance. There has been a recent advancement of several new drugs in this category and this number will soon grow as more drugs are reaching the end of their clinical trials. This article will discuss the nonhemostatic adverse effects of anticoagulants and antiplatelet drugs. As the adverse effects of bleeding and thrombosis will be excluded, this article will be in contrast to the typical discussions on the anticoagulant and antiplatelet drug classes.

  20. Effects of Agent's Repulsion in 2d Flocking Models

    NASA Astrophysics Data System (ADS)

    Moussa, Najem; Tarras, Iliass; Mazroui, M'hammed; Boughaleb, Yahya

    In nature many animal groups, such as fish schools or bird flocks, clearly display structural order and appear to move as a single coherent entity. In order to understand the complex behavior of these systems, many models have been proposed and tested so far. This paper deals with an extension of the Vicsek model, by including a second zone of repulsion, where each agent attempts to maintain a minimum distance from the others. The consideration of this zone in our study seems to play an important role during the travel of agents in the two-dimensional (2D) flocking models. Our numerical investigations show that depending on the basic ingredients such as repulsion radius (R1), effect of density of agents (ρ) and noise (η), our nonequilibrium system can undergo a kinetic phase transition from no transport to finite net transport. For different values of ρ, kinetic phase diagrams in the plane (η ,R1) are found. Implications of these findings are discussed.

  1. [A review of the effect of tooth bleaching agents on oral microbes].

    PubMed

    Zhang, Bo; Huo, Sibei; Liu, Shiyu; Li, Mingyun

    2016-02-01

    Tooth bleaching agents contain powerful oxidizing agents, which serve as the main part of bleaching agents because of its release of effective bleaching component. It has been a hot topic whether tooth bleaching agents exert negative influence on oral health. In order to provide train of thoughts and reference for further clinical researches and treatments, this review paper focuses on bleaching agents' effects on the growth of oral microbes and the formation of biofilms.

  2. Effects of bulking agents on food waste composting.

    PubMed

    Chang, James I; Chen, Y J

    2010-08-01

    The effects of rice husk, sawdust and rice bran on the composting process of food waste were studied in a 180-L laboratory composter based on a mixture experimental design. Linear and quadratic models of seven important process characteristics (composting and acidification times, lowest and final pH values, highest temperature, the water-soluble organic carbon to water-soluble organic nitrogen (C(OW)/N(OW) ratio), and the water-soluble organic carbon to total organic nitrogen (C(OW)/N(OT)) ratio) in terms of fractional compositions of bulking agents as well as the water absorption capacity and the free air space of the composting matrix were developed.

  3. Effect of certain anesthetic agents on mallard ducks

    USGS Publications Warehouse

    Cline, D.R.; Greenwood, R.J.

    1972-01-01

    Four anesthetic agents used in human or veterinary medicine and 3 experimental anesthetic preparations were evaluated for effectiveness in inducing narcosis when administered orally to game-farm mallard ducks (Anas platyrhynchos).Tribromoethanol was the only compound to satisfy criteria of initial tests. Mean duration of the induction, immobilization, and recovery periods was 2.4 minutes, 8.7 minutes, and 1.3 hours, respectively, at the median effective dosage for immobilization (ED50; 100 mg./kg. of body weight). The median lethal dosage (LD50) was 400 mg./kg. of body weight.Tribromoethanol was also tested on mallards during the reproductive season. Effects on the hatchability of eggs or the survival of young were not detected.

  4. C60(Nd) nanoparticles enhance chemotherapeutic susceptibility of cancer cells by modulation of autophagy

    NASA Astrophysics Data System (ADS)

    Wei, Pengfei; Zhang, Li; Lu, Yang; Man, Na; Wen, Longping

    2010-12-01

    Autophagy, an evolutionally conserved intracellular process degrading cytoplasmic proteins and organelles for recycling, has become one of the most remarkable strategies applied in cancer research. The fullerene C60 nanoparticle (nC60) has been shown to induce autophagy and sensitize chemotherapeutic killing of cancer cells, but the details still remain unknown. Here we show that a water-dispersed nanoparticle solution of derivatized fullerene C60, C60(Nd) nanoparticles (nC60(Nd)), has greater potential in inducing autophagy and sensitizing chemotherapeutic killing of both normal and drug-resistant cancer cells than nC60 does in an autophagy-dependent fashion. Additionally we further demonstrated that autophagy induced by nC60/C60(Nd) and Rapamycin had completely different roles in cancer chemotherapy. Our results, for the first time, revealed a novel and more potent derivative of the C60 nanoparticle in enhancing the cytotoxicity of chemotherapeutic agents and reducing drug resistance through autophagy modulation, which may ultimately lead to novel therapeutic strategies in cancer therapy.

  5. Effectiveness of three bulking agents for food waste composting

    SciTech Connect

    Adhikari, Bijaya K.; Barrington, Suzelle Martinez, Jose; King, Susan

    2009-01-15

    Rather than landfilling, composting the organic fraction of municipal solid wastes recycles the waste as a safe and nutrient enriched soil amendment, reduces emissions of greenhouse gases and generates less leachate. The objective of this project was to investigate the composting effectiveness of three bulking agents, namely chopped wheat (Triticum) straw, chopped mature hay consisting of 80% timothy (milium) and 20% clover (triphullum) and pine (pinus) wood shavings. These bulking agents were each mixed in duplicates at three different ratios with food waste (FW) and composted for 10 days using prototype in-vessel composters to observe their temperature and pH trends. Then, each mixture was matured in vertical barrels for 56 days to measure their mass loss and final nutrient content and to visually evaluate their level of decomposition. Chopped wheat straw (CWS) and chopped hay (CH) were the only two formulas that reached thermophilic temperatures during the 10 days of active composting when mixed with FW at a wet mass ratio of 8.9 and 8.6:1 (FW:CWS and FW:CH), respectively. After 56 days of maturation, these two formulas were well decomposed with no or very few recognizable substrate particles, and offered a final TN exceeding the original. Wood shavings (WS) produced the least decomposed compost at maturation, with wood particles still visible in the final product, and with a TN lower than the initial. Nevertheless, all bulking agents produced compost with an organic matter, TN, TP and TK content suitable for use as soil amendment.

  6. Novel Resveratrol and 5-Fluorouracil Coencapsulated in PEGylated Nanoliposomes Improve Chemotherapeutic Efficacy of Combination against Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Sethuraman, Swaminathan

    2014-01-01

    Increasing consumption of tobacco and alcohol has led to a steady increase in the incidence of head and neck cancers in Asia. The drawbacks associated with the existing chemotherapeutic and surgical interventions have necessitated the development of a safer alternative for therapy of head and neck cancers. In this study we have explored the synergistic therapeutic potential of a phytochemical and chemotherapeutic agent using PEGylated liposomes as a delivery vehicle. Resveratrol and 5-fluorouracil were successfully coencapsulated in a single PEGylated nanoliposome. The thermal analysis and the nuclear magnetic resonance results revealed that resveratrol localized near the glycerol backbone of the liposomal membrane while 5-fluorouracil localized closer to the phosphate moiety, which influenced the release kinetics of both drugs. The nanoformulation was tested in vitro on a head and neck cancer cell line NT8e and was found to exhibit a GI50 similar to that of free 5-fluorouracil. Further, gene expression studies showed that the combination of resveratrol and 5-fluorouracil exhibited different effects on different genes that may influence the net antagonistic effect. The coencapsulation of resveratrol and 5-fluorouracil in a liposomal nanocarrier improved the cytotoxicity in comparison with the free drug combination when tested in vitro. PMID:25114900

  7. Common Adverse Effects of Anti-TNF Agents on Gestation

    PubMed Central

    Antsaklis, Panagiotis; Galanopoulos, Nikolaos; Kontomanolis, Emmanuel

    2016-01-01

    Autoimmune disease has affected up to 50 million Americans, according to the American Autoimmune Related Diseases Association (AARDA) and 75 percent of those affected are women. These inflammatory diseases have variable activity and a lot of women will have to undergo major therapies during and after pregnancy. Many of the women suffering from these disease will improve during gestation. However a lot of women will require continuation of disease-modifying therapies (i.e., biological therapies) throughout pregnancy and post-partum involving many risks. In the past decade all gaze turned to biological therapies, as an attempt, to obtain even more effective medications in order to suppress the exacerbation of autoimmune disease, even at the most unfit circumstances such as pregnancy. The results are both satisfying and promising since increasingly proven thoughts prevail on making anti-TNF agents first-line medications, clearing up the limited knowledge over human influence. The purpose of this review is to summarize the results of the reports with the highest and representative range of patients of the last decade involving the use of anti-TNF agents during pregnancy. PMID:28044081

  8. Susceptibility of Helicobacter pylori to antimicrobial agents: effect of sulglycotide.

    PubMed

    Piotrowski, J; Murty, V L; Slomiany, A; Slomiany, B L

    1995-03-01

    H. pylori is regarded as a primary etiologic factor in gastric disease and the therapies now include a combination of antimicrobial agents with antiulcer drugs. Here, the effect of a new gastroprotective agent, sulglycotide, on the in vitro anti-H. pylori activity of metronidazole, erythromycin, tetracycline, and amoxycillin was assessed. The assays in the absence of sulglycotide gave MIC value 0.10mg/L for erythromycin, 0.12mg/L for amoxycillin, 0.15mg/L for tetracycline and 14mg/L for metronidazole, while sulglycotide alone gave MIC value of 20mg/L. The sulglycotide at its optimal dose (5mg/L) evoked a 4-fold enhancement in the MIC of amoxycillin, 5-fold in tetracycline, and 8.3-fold in erythromycin, while the MIC of metronidazole improved 3.5-fold at 10mg/L sulglycotide. The results point towards the advantage of combination therapy of sulglycotide and antibiotics for H. pylori eradication.

  9. Antibody–drug conjugates as novel anti-cancer chemotherapeutics

    PubMed Central

    Peters, Christina; Brown, Stuart

    2015-01-01

    Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics. PMID:26182432

  10. Inhibition of poly(ADP-ribose) polymerase-1 or poly(ADP-ribose) glycohydrolase individually, but not in combination, leads to improved chemotherapeutic efficacy in HeLa cells

    PubMed Central

    FENG, XIAOXING; KOH, DAVID W.

    2013-01-01

    The genome-protecting role of poly(ADP-ribose) (PAR) has identified PAR polymerase-1 (PARP-1) and PAR glycohydrolase (PARG), two enzymes responsible for the synthesis and hydrolysis of PAR, as chemotherapeutic targets. Each has been previously individually evaluated in chemotherapy, but the effects of combination PARP-1 and PARG inhibition in cancer cells are not known. Here we determined the effects of the inhibition of PARP-1 and the absence or RNAi knockdown of PARG on PAR synthesis, cell death after chemotherapy and long-term viability. Using three experimental/clinical PARP-1 inhibitors in PARG-null cells, we show decreased levels of PAR and increased short-term and long-term viability with each inhibitor, with the exception of DPQ. Treatment with the experimental chemotherapeutic agent, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), led to increased cell death in PARG-null cells, but decreased cell death when pretreated with each PARP-1 inhibitor. Similar results were observed in MNNG-treated HeLa cells, where RNAi knockdown of PARG or pretreatment with ABT-888 led to increased HeLa cell death, whereas combination PARG RNAi knockdown + ABT-888 failed to produce increased cell death. The results demonstrate the ability of the PARP-1 inhibitors to decrease PAR levels, maintain viability and decrease PAR-mediated cell death after chemotherapeutic treatment in the absence of PARG. Further, the results demonstrate that the combination of PARP-1 and PARG inhibition in chemotherapy does not produce increased HeLa cell death. Thus, the results indicate that inhibiting both PARP-1 and PARG, which both are chemotherapeutic targets that increase cancer cell death, does not lead to synergistic cell death in HeLa cells. Therefore, strategies that target PAR metabolism for the improved treatment of cancer may be required to target PARP-1 and PARG individually in order to optimize cancer cell death. PMID:23254695

  11. Curcumin potentiates the effect of chemotherapy against acute lymphoblastic leukemia cells via downregulation of NF-κB

    PubMed Central

    Pimentel-Gutiérrez, Helia Judith; Bobadilla-Morales, Lucina; Barba-Barba, César Cenobio; Ortega-De-La-Torre, Citlalli; Sánchez-Zubieta, Fernando Antonio; Corona-Rivera, Jorge Román; González-Quezada, Betsy Annel; Armendáriz-Borunda, Juan S.; Silva-Cruz, Rocío; Corona-Rivera, Alfredo

    2016-01-01

    Acute lymphoblastic leukemia (ALL) accounts for 30% of all pediatric cancers. Currently available treatments exhibit toxicity and certain patients may develop resistance. Thus, less toxic and chemoresistance-reversal agents are required. In the present study, the potential effect of curcumin, a component of Curcuma longa, as a pharmacological co-adjuvant of several chemotherapeutic agents against ALL, including prednisone, 6-mercaptopurine, dexamethasone, cyclophosphamide, l-asparaginase, vincristine, daunorubicin, doxorubicin, methotrexate and cytarabine, was investigated in the REH ALL cell line cultures treated in combination with chemotherapeutic agents and curcumin. The results of cell viability, gene expression and activation of NF-κB and caspase 3 indicated that curcumin potentiates the anticancer effects of the aforementioned chemotherapeutic agents in the REH ALL cell line. Following treatment with the above chemotherapeutic agents, curcumin enhanced caspase-3 activation and downregulated nuclear factor-kappa B (NF-κB) activation. Curcumin also downregulated the oxidative stress induced by certain chemotherapies. Notably, curcumin did not affect the gene expression of cell survival proteins such as B-cell lymphoma (Bcl)-2, Bcl-extra large, survivin, c-Myc and cyclin D1, which are regulated by the NF-κB transcription factor. In conclusion, curcumin has the potential to improve the effect of chemotherapeutic agents against ALL. PMID:27895780

  12. Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices.

    PubMed

    Casey, A; Gargotti, M; Bonnier, F; Byrne, H J

    2016-06-01

    The interest in the use of 3D matrices for in vitro analysis, with a view to increasing the relevance of in vitro studies and reducing the dependence on in vivo studies, has been growing in recent years. Cells grown in a 3D in vitro matrix environment have been reported to exhibit significantly different properties to those in a conventional 2D culture environment. However, comparison of 2D and 3D cell culture models have recently been noted to result in differing responses of cytotoxic assays, without any associated change in viability. The effect was attributed to differing conversion rates and effective concentrations of the resazurin assay in 2D and 3D environments, rather than differences in cellular metabolism. In this study, the efficacy of a chemotherapeutic agent, doxorubicin, is monitored and compared in conventional 2D and 3D collagen gel exposures of immortalized human cervical cells. Viability was monitored with the aid of the Alamar Blue assay and drug internalisation was verified using confocal microscopy. Drug uptake and retention within the collagen matrix was monitored by absorption spectroscopy. The viability studies showed apparent differences between the 2D and 3D culture systems, the differences attributed in part to the physical transition from 2D to a 3D environment causing alterations to dye resazurin uptake and conversion rates. The use of 3D culture matrices has widely been interpreted to result in "reduced" toxicity or cellular "resistance" to the chemotherapeutic agent. The results of this study show that the reduced efficiency of the drug to cells grown in the 3D environment can be accounted for by a sequential reduction of the effective concentration of the test compound and assay. This is due to absorption within the collagen gel inducing a higher uptake of both drug and assay thereby influencing the toxic impact of the drug and conversion rate of resazurin, and. The increased effective surface area of the cell exposed to the drug

  13. Signaling via the anti-CD30 mAb SGN-30 sensitizes Hodgkin's disease cells to conventional chemotherapeutics.

    PubMed

    Cerveny, C G; Law, C-L; McCormick, R S; Lenox, J S; Hamblett, K J; Westendorf, L E; Yamane, A K; Petroziello, J M; Francisco, J A; Wahl, A F

    2005-09-01

    SGN-30, a monoclonal antibody with activity against CD30+ malignancies, is currently in phase II clinical evaluation for treatment of Hodgkin's disease (HD) and anaplastic large cell lymphoma. The mechanisms underlying SGN-30's antitumor activity were investigated using cDNA array of L540 cells. SGN-30 treatment activated NF-kappaB and modulation of several messages including the growth regulator p21WAF1/CIP1 (p21) and cellular adhesion marker ICAM-1. p21 protein levels increased coincident with growth arrest and Annexin V/PI staining in treated HD cells. To determine if SGN-30-induced growth arrest would sensitize tumor cells to chemotherapeutics used against HD, L540cy and L428 cells were exposed to SGN-30 in combination with a panel of cytotoxic agents and resultant interactions quantified by the Combination Effects Method. Interactions between SGN-30 and all cytotoxic agents examined were additive or better. These in vitro data translated to increased efficacy of SGN-30 and bleomycin against L540cy tumor xenografts. In addition to direct cell killing, SGN-30 affects growth arrest and drug sensitization through growth regulating and proapoptotic machinery. Importantly, these data suggest that SGN-30 can enhance the efficacy of standard chemotherapies used to treat patients with CD30+ malignancies.

  14. General effects of hyperosmolar agents on the endolymphatic sac.

    PubMed

    Erwall, C

    1988-11-01

    The effects of glycerol, urea and mannitol on the structure of the murine endolymphatic sac were investigated at various time intervals after their administration. Within 15 min after administration of glycerol and urea the lumen of the endolymphatic sac was partially collapsed and the density of its contents was increased. At the same time many light epithelial cells displayed abundant intracytoplasmic granules containing floccular and/or lamellar material. A similar type of material was observed in the lumen in close proximity to these cells. This suggested that macromolecular substances were secreted into the endolymphatic sac lumen from these cells. Mannitol induced similar changes, though less pronounced. It is proposed that the changes in the endolymphatic sac following systemic administration of hyperosmolar substances reflect an ability of the endolymphatic sac to compensate for endolymphatic volume and pressure changes caused by these agents.

  15. Effect of two desensitizing agents on dentin permeability in vitro

    PubMed Central

    ISHIHATA, Hiroshi; KANEHIRA, Masafumi; FINGER, Werner J.; TAKAHASHI, Hidekazu; TOMITA, Makoto; SASAKI, Keiichi

    2017-01-01

    Abstract Objective The aim of this in vitro study was to investigate the effect of two desensitizing agents and water on hydraulic conductance in human dentin. Material and Methods GLUMA Desensitizer PowerGel (GLU) contains glutaraldehyde (GA) and 2-hydroxyethyl methacrylate (HEMA), and Teethmate Desensitizer (TD) is a powder comprising tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous (DCPA) that is mixed with water. Deionized water was used as a negative control (CTR). Thirty discs with a thickness of 1.2 mm were cut from the coronal dentin of the third molars and cleaned with 0.5 M EDTA (pH 7.4). After being mounted in a split-chamber device, the discs were pressurized with water at 1 kPa and 3 kPa in order to measure flow rates with a highly sensitive micro-flow sensor and to calculate hydraulic conductance as a baseline value (BL). Following the application of GLU, TD, and CTR (n=10), hydraulic conductance was remeasured with intermittent storage in water after 15 min, 1 d, 1 w, and 1 m. Reduction in permeability (PR%) was calculated from hydraulic conductance. Data were statistically analyzed using nonparametric methods (α<0.05). Representative discs were inspected by SEM. Results PR% for GLU and TD were 30-50% 15 min and 1 m after their application. Post hoc tests indicated that PR% of CTR was significantly greater than those of GLU and TD at all time points tested. The PR% of GLU and TD were not significantly different. SEM examinations showed noncollapsed collagen meshes at the tubular entrances after GLU, and crystalline precipitates occluding the tubular orifices after TD, whereas CTR specimens showed typical patterns of etched dentin. Conclusions The present study on hydraulic conductance in dentin discs treated with two chemically different desensitizing agents and water as a control demonstrated that both products may be characterized as effective. PMID:28198974

  16. Molecular effects of supraphysiological doses of doping agents on health.

    PubMed

    Imperlini, Esther; Mancini, Annamaria; Alfieri, Andreina; Martone, Domenico; Caterino, Marianna; Orrù, Stefania; Buono, Pasqualina

    2015-06-01

    Performance-enhancing drugs (PEDs) gained wide popularity not only among sportsmen but also among specific subsets of population, such as adolescents. Apart from their claimed effects on athletic performance, they are very appealing due to the body shaping effect exerted on fat mass and fat-free mass. Besides the "underestimated" massive misuse of PEDs, the short- as well as long-term consequences of such habits remain largely unrecognized. They have been strictly associated with serious adverse effects, but molecular mechanisms are yet to be elucidated. Here, we analyze the current understanding of the molecular effects of supraphysiological doses of doping agents in healthy biological systems, at genomic and proteomic levels, in order to define the molecular sensors of organ/tissue impairment, determined by their misuse. The focus is put on the anabolic androgenic steroids (AASs), specifically testosterone (T) and its most potent derivative dihydrotestosterone (DHT), and on the peptide hormones, specifically the growth hormone (GH) and the insulin-like growth factor-1 (IGF-1). A map of molecular targets is defined and the risk incidence for human health is taken into account.

  17. Chronic chemotherapeutic stress promotes evolution of stemness and WNT/beta-catenin signaling in colorectal cancer cells: implications for clinical use of WNT-signaling inhibitors

    PubMed Central

    Ayadi, Meriam; Bouygues, Anaïs; Ouaret, Djamila; Ferrand, Nathalie; Chouaib, Salem; Thiery, Jean-Paul; Muchardt, Christian; Sabbah, Michèle; Larsen, Annette K

    2015-01-01

    Most solid tumors contain a subfraction of cells with stem/progenitor cell features. Stem cells are naturally chemoresistant suggesting that chronic chemotherapeutic stress may select for cells with increased “stemness”. We carried out a comprehensive molecular and functional analysis of six independently selected colorectal cancer (CRC) cell lines with acquired resistance to three different chemotherapeutic agents derived from two distinct parental cell lines. Chronic drug exposure resulted in complex alterations of stem cell markers that could be classified into three categories: 1) one cell line, HT-29/5-FU, showed increased “stemness” and WNT-signaling, 2) three cell lines showed decreased expression of stem cell markers, decreased aldehyde dehydrogenase activity, attenuated WNT-signaling and lost the capacity to form colonospheres and 3) two cell lines displayed prominent expression of ABC transporters with a heterogeneous response for stem cell markers. While WNT-signaling could be attenuated in the HT-29/5-FU cells by the WNT-signaling inhibitors ICG-001 and PKF-118, this was not accompanied by any selective growth inhibitory effect suggesting that the cytotoxic activity of these compounds is not directly linked to WNT-signaling inhibition. We conclude that classical WNT-signaling inhibitors have toxic off-target activities that need to be addressed for clinical development. PMID:26041882

  18. Social effects of an anthropomorphic help agent: humans versus computers.

    PubMed

    David, Prabu; Lu, Tingting; Kline, Susan; Cai, Li

    2007-06-01

    The purpose of this study was to examine perceptions of fairness of a computer-administered quiz as a function of the anthropomorphic features of the help agent offered within the quiz environment. The addition of simple anthropomorphic cues to a computer help agent reduced the perceived friendliness of the agent, perceived intelligence of the agent, and the perceived fairness of the quiz. These differences were observed only for male anthropomorphic cues, but not for female anthropomorphic cues. The results were not explained by the social attraction of the anthropomorphic agents used in the quiz or by gender identification with the agents. Priming of visual cues provides the best account of the data. Practical implications of the study are discussed.

  19. Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer.

    PubMed

    Mehta, Amit; Zhang, Lisa; Boufraqech, Myriem; Zhang, Yaqin; Patel, Dhaval; Shen, Min; Kebebew, Electron

    2015-06-01

    Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.

  20. Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

    PubMed Central

    Fagone, Paolo; Caltabiano, Rosario; Russo, Andrea; Lupo, Gabriella; Anfuso, Carmelina Daniela; Basile, Maria Sofia; Longo, Antonio; Nicoletti, Ferdinando; De Pasquale, Rocco; Libra, Massimo; Reibaldi, Michele

    2017-01-01

    Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma. PMID:28303962

  1. Identification of novel chemotherapeutic strategies for metastatic uveal melanoma.

    PubMed

    Fagone, Paolo; Caltabiano, Rosario; Russo, Andrea; Lupo, Gabriella; Anfuso, Carmelina Daniela; Basile, Maria Sofia; Longo, Antonio; Nicoletti, Ferdinando; De Pasquale, Rocco; Libra, Massimo; Reibaldi, Michele

    2017-03-17

    Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS(2) web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.

  2. The Effects of Animated Agents on Students' Achievement and Attitudes

    ERIC Educational Resources Information Center

    Unal-Colak, Figen; Ozan, Ozlem

    2012-01-01

    Animated agents are electronic agents that interact with learners through voice, visuals or text and that carry human-like characteristics such as gestures and facial expressions with the purpose of creating a social learning environment, and provide information and guidance and when required feedback and motivation to students during their…

  3. Using Animated Agents in Learner-Controlled Training: The Effects of Design Control

    ERIC Educational Resources Information Center

    Behrend, Tara S.; Thompson, Lori Foster

    2012-01-01

    Animated agents have the potential to increase engagement and learning during online training by acting as personalized tutors. However, little is known about the conditions that make these agents most effective. In this study, 183 e-learners completed a Microsoft Excel training course. Approximately half were assigned an agent with predetermined…

  4. Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature

    PubMed Central

    Melchionda, Fraia; Pession, Andrea

    2016-01-01

    T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on the ASNS gene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of the ASNS gene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with low ASNS expression due to hypermethylation of the ASNS promoter, while it did not restore sensitivity in the resistant cell lines characterized by higher ASNS expression. PMID:28003999

  5. Resveratrol enhances the inotropic effect but inhibits the proarrhythmic effect of sympathomimetic agents in rat myocardium

    PubMed Central

    2017-01-01

    Background Resveratrol is a cardioprotective agent with known antiarrhythmic effects that has recently been shown to inhibit phosphodiesterase (PDE) enzyme activity. Thus, it is possible that resveratrol increases the inotropic effect of sympathomimetic agents, as PDE inhibitors do but, unlike other PDE inhibitors, its effect may not be accompanied by proarrhythmia due to its antiarrhythmic action. This work is aimed to test this hypothesis. Methods This is an “in vitro” concentration-response relationship study. The effects of noradrenaline, tyramine and isoproterenol, alone or in combination with either resveratrol or with the typical PDE inhibitor 3-isobutylmethylxantine (IBMX), were studied in electrically driven strips of right ventricle or in the spontaneously beating free wall of the right ventricle of rat heart in order to investigate inotropic or proarrhythmic effects respectively. Also, the effects of resveratrol or IBMX on the sinoatrial node rate were examined in the isolated right atria of rat heart. Results Resveratrol (10 µM and 100 µM) produces a leftward shift in the concentration-response curves for the contractile effects of noradrenaline, tyramine or isoproterenol and reduces the –log EC50 values of these three agents. IBMX produces similar effects. The spontaneous ventricular beating rate was increased by all three compounds, an effect that was further enhanced by the addition of IBMX. In contrast, resveratrol (100 µM) abolished the effects of these sympathomimetic agents on the ventricular rate. Resveratrol (1–100 µM) had no effect on the sinoatrial node rate, while IBMX produce a concentration dependent sinoatrial tachycardia. Discussion Taken together, the finding, indicate that resveratrol, like the PDE inhibitor IBMX enhances the contractile effects of sympathomimetic agents but, in contrast to IBMX, it does not enhance their proarrhythmic effect or produce sinoatrial tachycardia. This is most probably consequence of the

  6. Effect of radioprotective agents on X-ray cataracts

    SciTech Connect

    Reddy, V.N.; Ikebe, H.; Giblin, F.J.; Clark, J.I.; Livesey, J.C. )

    1989-01-01

    The effect of some protective agents on cataract development is briefly reviewed and new evidence is presented on the efficacy of a phosphorothioate compound (Amifostine) in inhibiting the development of X-ray-induced cataract. Morphological studies showed that at the end of 4 months, lenses from X-irradiated rats which had not received any drugs showed liquefaction in the equatorial region and at the posterior pole, as well as a marked swelling of the fibers in the anterior cortex. Animals which received 1.16g/kg of WR77913 showed considerable protection against the development of radiation induced cataracts with morphological changes in the lens being less severe than in animals receiving no drugs. When animals were treated with 0.5g/kg of Amifostine (WR2721) the lenses showed much greater protection against cataract development than with WR77913. Amifostine appears to be more effective than WR77913 in inhibiting X-ray-induced cataract development. 20 refs.

  7. The effect of alkylating agents on male rat fertility

    PubMed Central

    Jackson, H.; Fox, B. W.; Craig, A. W.

    1959-01-01

    The effects of tumour inhibitory doses of tretamine (triethylenemelamine), busulphan, and melphalan on the fertility of male rats have been examined. The aromatic nitrogen mustard, melphalan, was inactive, but busulphan has a highly selective action on spermatogenesis which contrasts strikingly with that of tretamine. The main action of tretamine was exerted upon spermatocytes or spermatids, but, with increasing dose, the effects spread to involve a wide range of spermatogenic cells including mature sperm, so that infertility could be induced very rapidly. Busulphan, however, interfered with the development of spermatogonia for several weeks, although other germinal cells were unaffected and continued to develop into mature spermatozoa. This accounted for the continuation of normal fertility for 7 weeks after a dose, before sterility suddenly developed. The antifertility activity of tretamine could be simulated by a variety of other ethyleneimino compounds, potency being greatest in trifunctional and least in monofunctional compounds. The latter were, however, very destructive to the seminiferous epithelium with increasing dose. In the rat, there appeared to be no definite relationship between the ability of alkylating substances to interfere with the activity of normal and pathological proliferating tissues, as represented by the germinal epithelium, haematopoietic, and tumour tissue. Although carcinogenicity was a biological property of alkylating agents, other chemical types of carcinogen did not interfere with fertility. ImagesFIG. 2aFIG. 2bFIG. 2c PMID:13662565

  8. Stabilizing Agents for Drug Nanocrystals: Effect on Bioavailability

    PubMed Central

    Tuomela, Annika; Hirvonen, Jouni; Peltonen, Leena

    2016-01-01

    Drug nanocrystals are a versatile option for drug delivery purposes, and while the number of poorly soluble drug materials is all the time increasing, more research in this area is performed. Drug nanocrystals have a simple structure—a solid drug core is surrounded by a layer of stabilizing agent. However, despite the considerably simple structure, the selection of an appropriate stabilizer for a certain drug can be challenging. Mostly, the stabilizer selection is based purely on the requirement of physical stability, e.g., maintaining the nanosized particle size as long as possible after the formation of drug nanocrystals. However, it is also worth taking into account that stabilizer can affect the bioavailability in the final formulation via interactions with cells and cell layers. In addition, formation of nanocrystals is only one process step, and for the final formulation, more excipients are often added to the composition. The role of the stabilizers in the final formulation can be more than only stabilizing the nanocrystal particle size. A good example is the stabilizer’s role as cryoprotectant during freeze drying. In this review, the stabilizing effect, role of stabilizers in final nanocrystalline formulations, challenges in reaching in vitro–in vivo correlation with nanocrystalline products, and stabilizers’ effect on higher bioavailability are discussed. PMID:27213435

  9. The Cell’s Nucleolus: an Emerging Target for Chemotherapeutic Intervention

    PubMed Central

    Pickard, Amanda J.

    2013-01-01

    The transient nucleolus plays a central role in the upregulated synthesis of ribosomal RNA (rRNA) to sustain ribosome biogenesis, a hallmark of aberrant cell growth. This function, in conjunction with its unique pathohistological features in malignant cells and its ability to mediate apoptosis, renders this subnuclear structure a potential target for chemotherapeutic agents. In this Minireview, structurally and functionally diverse small molecules are discussed that have been reported to either interact with the nucleolus directly or perturb its function indirectly by acting on its dynamic components. These molecules include all major classes of nucleic acid-targeted agents, antimetabolites, kinase inhibitors, anti-inflammatory drugs, natural product antibiotics, oligopeptides, as well asnano-sized particles. Together, these molecules are invaluable probes of structure and function of the nucleolus. They also provide a unique opportunity to develop novel strategies for more selective and therefore better tolerated chemotherapeutic intervention. In this regard, inhibition of RNA polymerase I-mediated rRNA synthesis appears to be a promising mechanism of cancer cell kill. The recent development of molecules targeted at G-quadruplex forming rRNA gene sequences, which are currently undergoing clinical trials, seems to attest to the success of this approach. PMID:23881648

  10. Multidrug Resistance-Associated Protein 2 Expression Is Upregulated by Adenosine 5’-Triphosphate in Colorectal Cancer Cells and Enhances Their Survival to Chemotherapeutic Drugs

    PubMed Central

    Vinette, Valérie; Placet, Morgane; Arguin, Guillaume; Gendron, Fernand-Pierre

    2015-01-01

    Extracellular adenosine 5’-triphosphate (ATP) is a signaling molecule that induces a plethora of effects ranging from the regulation of cell proliferation to modulation of cancerous cell behavior. In colorectal cancer, ATP was reported to stimulate epithelial cell proliferation and possibly promote resistance to anti-cancer treatments. However, the exact role of this danger-signaling molecule on cancerous intestinal epithelial cells (IECs) in response to chemotherapeutic agents remains unknown. To address how ATP may influence the response of cancerous IECs to chemotherapeutic agents, we used Caco-2 cells, which display enterocyte-like features, to determine the effect of ATP on the expression of multidrug resistance-associated protein 2 (MRP2). Gene and protein expression were determined by quantitative real-time PCR (qRT-PCR) and Western blotting. Resistance to etoposide, cisplatin and doxorubicin was determined by MTT assays in response to ATP stimulation of Caco-2 cells and in cells for which MRP2 expression was down-regulated by shRNA. ATP increased the expression of MRP2 at both the mRNA and protein levels. MRP2 expression involved an ATP-dependent stimulation of the MEK/ERK signaling pathway that was associated with an increase in relative resistance of Caco-2 cells to etoposide. Abolition of MRP2 expression using shRNA significantly reduced the protective effect of MRP2 toward etoposide as well as to cisplatin and doxorubicin. This study describes the mechanism by which ATP may contribute to the chemoresistance of cancerous IECs in colorectal cancer. Given the heterogeneity of colorectal adenocarcinoma responses to anti-cancer drugs, these findings call for further study to understand the role of P2 receptors in cancer drug therapy and to develop novel therapies aimed at regulating P2 receptor activity. PMID:26295158

  11. Enhanced delivery of the RAPTA-C macromolecular chemotherapeutic by conjugation to degradable polymeric micelles.

    PubMed

    Blunden, Bianca M; Lu, Hongxu; Stenzel, Martina H

    2013-12-09

    Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein reaction and reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell uptake of these polymeric moieties was tested on ovarian cancer A2780, A2780cis, and Ovcar-3 cell lines. Confocal microscopy images confirmed cell uptake of the micelles into the lysosome of the cells, indicative of an endocytic pathway. On average, a 10-fold increase in toxicity was found for the macromolecular drugs when compared to the RAPTA-C molecule. Furthermore, the cell uptake of ruthenium was analyzed and a significant increase was found for the micelles compared to RAPTA-C. Notably, micelles prepared from the polymer containing fewer HEA units had the highest cytotoxicity, the best cell uptake of ruthenium and were highly effective in suppressing the colony-forming ability of cells.

  12. Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

    PubMed

    Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

    2015-02-01

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

  13. Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents Against Lung Cancer

    DTIC Science & Technology

    2014-10-01

    effectively and accurately replicate crosslinked DNA lesions such as thymine dimers and cisplatinated DNA (19-21). A third group of DNA polymerases...lines correlates with resistance to chemotherapeutic agents such as cisplatin which damage DNA (38). Furthermore, pol  overexpression is a poor... cisplatinated GG adduct (33). In this model, dCTP is properly paired with the first templating nucleobase via conventional hydrogen bonds. In general, our

  14. Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids

    PubMed Central

    Wang, Qilong; Zhuang, Xiaoying; Mu, Jingyao; Deng, Zhong-Bin; Jiang, Hong; Xiang, Xiaoyu; Wang, Baomei; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

    2015-01-01

    Although the use of nanotechnology for the delivery of a wide range of medical treatments has potential to reduce adverse effects associated with drug therapy, tissue-specific delivery remains challenging. Here we show that nanoparticles made of grapefruit-derived lipids, which we call grapefruit-derived nanovectors (GNVs), can transport chemotherapeutic agents, siRNA, DNA expression vectors and proteins to different types of cells. We demonstrate the in vivo targeting specificity of GNVs by co-delivering therapeutic agents with folic acid, which in turn leads to significantly increasing targeting efficiency to cells expressing folate receptors. The therapeutic potential of GNVs was further demonstrated by enhancing the chemotherapeutic inhibition of tumor growth in two tumor animal models. GNVs are less toxic than nanoparticles made of synthetic lipids and, when injected intravenously into pregnant mice, do not pass the placental barrier, suggesting they may be a useful tool for drug delivery. PMID:23695661

  15. Effects of 1,25(OH)2D3 on Cancer Cells and Potential Applications in Combination with Established and Putative Anti-Cancer Agents

    PubMed Central

    Abu el Maaty, Mohamed A.; Wölfl, Stefan

    2017-01-01

    The diverse effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the bio-active form of vitamin D, on cancer cell metabolism and proliferation has made it an interesting candidate as a supporting therapeutic option in cancer treatment. An important strategy in cancer therapy is the use of combination chemotherapy to overcome drug resistance associated with numerous anti-cancer agents and to provide better means of avoiding undesirable side effects. This complex strategy is widely adopted by oncologists and several established “cocktails” of chemotherapeutics are routinely administered to cancer patients. Among the principles followed in designing such treatment regimens is the use of drugs with different mechanisms of action to overcome the issue of tumor heterogeneity and to evade resistance. In light of the profound and diverse effects of 1,25(OH)2D3 reported by in vitro and in vivo studies, we discuss how these effects could support the use of this molecule in combination with “classical” cytotoxic drugs, such as platins and anti-metabolites, for the treatment of solid and hematological tumors. We also examine recent evidence supporting synergistic activities with other promising anti-cancer drug candidates, and postulate mechanisms through which 1,25(OH)2D3 may help evade chemoresistance. PMID:28124999

  16. Innovative agents in cancer prevention.

    PubMed

    Manson, Margaret M; Farmer, Peter B; Gescher, Andreas; Steward, William P

    2005-01-01

    There are many facets to cancer prevention: a good diet, weight control and physical activity, a healthy environment, avoidance of carcinogens such as those in tobacco smoke, and screening of populations at risk to allow early detection. But there is also the possibility of using drugs or naturally occurring compounds to prevent initiation of, or to suppress, tumour growth. Only a few such agents have been used to date in the clinic with any success, and these include non-steroidal anti-inflammatory drugs for colon, finasteride for prostate and tamoxifen or raloxifene for breast tumours. An ideal chemopreventive agent would restore normal growth control to a preneoplastic or cancerous cell population by modifying aberrant signalling pathways or inducing apoptosis (or both) in cells beyond repair. Characteristics for such an agent include selectivity for damaged or transformed cells, good bioavailability and more than one mechanism of action to foil redundancy or crosstalk in signalling pathways. As more research effort is being targeted towards this area, the distinction between chemotherapeutic and chemopreventive agents is blurring. Chemotherapeutic drugs are now being designed to target over- or under-active signalling molecules within cancer cells, a philosophy which is just as relevant in chemoprevention. Development of dietary agents is particularly attractive because of our long-standing exposure to them, their relative lack of toxicity, and encouraging indications from epidemiology. The carcinogenic process relies on the cell's ability to proliferate abnormally, evade apoptosis, induce angiogenesis and metastasise to distant sites. In vitro studies with a number of different diet-derived compounds suggest that there are molecules capable of modulating each of these aspects of tumour growth. However, on the negative side many of them have rather poor bioavailability. The challenge is to uncover their multiple mechanisms of action in order to predict their

  17. Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

    DTIC Science & Technology

    2005-04-01

    chemotherapeutic agents including cyclophosphamide, methotrexate, anthracycline, cytarabine , paclitaxel, and corticosteroids (28). To determine whether the...cyclophosphamide, methotrexate, anthracycline, cytarabine , paclitaxel, and corticosteroids (28). Sasaki et al reported that the level of Bcl-2 in cancer cells

  18. Multi-Chemotherapeutic Schedules Containing the pan-FGFR Inhibitor ARQ 087 are Safe and Show Antitumor Activity in Different Xenograft Models.

    PubMed

    Chilà, Rosaria; Hall G, Terence; Abbadessa, Giovanni; Broggini, Massimo; Damia, Giovanna

    2017-02-02

    ARQ 087 is a multi-tyrosine kinase inhibitor with potent activity against the FGFR receptor family, currently in Phase I clinical studies for the treatment of advanced solid tumors. The compound has a very safe profile and induces tumor regressions in FGFR-driven models. The feasibility of combining ARQ 087 with chemotherapy was investigated in FGFR deregulated human xenografts. Nude mice were transplanted subcutaneously with H1581, and when tumor masses reached 150 mg, were randomized to receive vehicle, ARQ 087, paclitaxel, carboplatin as single agents or in combination. Similar experimental conditions were applied in nude mice bearing SNU16 and MFE296 xenografts, with the inclusion of capecitabine in the former xenograft model. In the different xenograft models, the drugs given as single agents ranged from very active to partially active. The double combinations were more active than the single ones, but the triple combinations were the most active. In particular, the combination of ARQ 087 + paclitaxel + carboplatin in H1581 bearing mice was able to induce tumor regression in all the mice, with 6/8 mice tumor free at day 140 after tumor transplant. Of note, no toxic deaths nor premature stopping or delaying of drug administration were observed. The data herein reported demonstrated the feasibility of using xenografts models for poli-chemotherapeutic trials mimicking the best standard of care in treatment of specific tumor type and that ARQ 087, a new pan-FGFR inhibitor, can be safely combined with standard cytotoxic chemotherapeutic drugs with apparently no sign of cumulative toxicity and an associated increased antitumor effect.

  19. Engineering novel targeted nanoparticle formulations to increase the therapeutic efficacy of conventional chemotherapeutics against multiple myeloma

    NASA Astrophysics Data System (ADS)

    Ashley, Jonathan D.

    Multiple myeloma (MM) is a hematological malignancy which results from the uncontrolled clonal expansion of plasma cells within the body. Despite recent medical advances, this disease remains largely incurable, with a median survival of ˜7 years, owing to the development of drug resistance. This dissertation will explore new advances in nanotechnology that will combine the cytotoxic effects of small molecule chemotherapeutics with the tumor targeting capabilities of nanoparticles to create novel nanoparticle formulations that exhibit enhanced therapeutic indices in the treatment of MM. First, doxorubicin was surfaced conjugated onto micellar nanoparticles via an acid labile hydrazone bond to increase the drug accumulation at the tumor. The cell surface receptor Very Late Antigen-4 (VLA-4; alpha4beta1) is expressed on cancers of hematopoietic origin and plays a vital role in the cell adhesion mediated drug resistance (CAM-DR) in MM. Therefore, VLA-4 antagonist peptides were conjugated onto the nanoparticles via a multifaceted procedure to actively target MM cells and simultaneously inhibit CAM-DR. The micellar doxorubicin nanoparticles were able to overcome CAM-DR and demonstrated improved therapeutic index relative to free doxorubicin. In addition to doxorubicin, other classes of therapeutic agents, such as proteasome inhibitors, can be incorporated in nanoparticles for improved therapeutic outcomes. Utilizing boronic acid chemistry, bortezomib prodrugs were synthesized using a reversible boronic ester bond and then incorporated into liposomes. The different boronic ester bonds that could be potentially used in the synthesis of bortezomib prodrugs were screened based on stability using isobutylboronic acid. The liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity in MM cells in vitro, and dramatically reduced the non-specific toxicities associated with free bortezomib while maintaining significant tumor growth

  20. Effective Team Support: From Modeling to Software Agents

    NASA Technical Reports Server (NTRS)

    Remington, Roger W. (Technical Monitor); John, Bonnie; Sycara, Katia

    2003-01-01

    The purpose of this research contract was to perform multidisciplinary research between CMU psychologists, computer scientists and engineers and NASA researchers to design a next generation collaborative system to support a team of human experts and intelligent agents. To achieve robust performance enhancement of such a system, we had proposed to perform task and cognitive modeling to thoroughly understand the impact technology makes on the organization and on key individual personnel. Guided by cognitively-inspired requirements, we would then develop software agents that support the human team in decision making, information filtering, information distribution and integration to enhance team situational awareness. During the period covered by this final report, we made substantial progress in modeling infrastructure and task infrastructure. Work is continuing under a different contract to complete empirical data collection, cognitive modeling, and the building of software agents to support the teams task.

  1. An Agent-Based Intervention to Assist Drivers Under Stereotype Threat: Effects of In-Vehicle Agents' Attributional Error Feedback.

    PubMed

    Joo, Yeon Kyoung; Lee-Won, Roselyn J

    2016-10-01

    For members of a group negatively stereotyped in a domain, making mistakes can aggravate the influence of stereotype threat because negative stereotypes often blame target individuals and attribute the outcome to their lack of ability. Virtual agents offering real-time error feedback may influence performance under stereotype threat by shaping the performers' attributional perception of errors they commit. We explored this possibility with female drivers, considering the prevalence of the "women-are-bad-drivers" stereotype. Specifically, we investigated how in-vehicle voice agents offering error feedback based on responsibility attribution (internal vs. external) and outcome attribution (ability vs. effort) influence female drivers' performance under stereotype threat. In addressing this question, we conducted an experiment in a virtual driving simulation environment that provided moment-to-moment error feedback messages. Participants performed a challenging driving task and made mistakes preprogrammed to occur. Results showed that the agent's error feedback with outcome attribution moderated the stereotype threat effect on driving performance. Participants under stereotype threat had a smaller number of collisions when the errors were attributed to effort than to ability. In addition, outcome attribution feedback moderated the effect of responsibility attribution on driving performance. Implications of these findings are discussed.

  2. The Effect of an MSN Agent on Learning Community and Achievement

    ERIC Educational Resources Information Center

    Hwang, Wu-Yuin; Huang, Yueh-Min; Wu, Sheng-Yi

    2011-01-01

    The use of instant messaging to support e-learning will continue to gain importance because of its speed, effectiveness, and low cost. This study developed an MSN agent to mediate and facilitate students' learning in a Web-based course. The students' acceptance of the MSN agent and its effect on learning community identification and learning…

  3. In Search of Pedagogical Agents' Modality and Dialogue Effects in Open Learning Environments

    ERIC Educational Resources Information Center

    Clarebout, Geraldine; Elen, Jan

    2007-01-01

    The aims of the present studies were to test the generalizability of the modality and dialogue effect to open learning environments, previously found by Moreno and Mayer (e.g., Moreno, Mayer & Lester, 2001) with an agent providing metacognitive support. As an extension, the agent's continuous presence effect on learning was also tested. Three…

  4. An in vitro screening method to evaluate chemicals as potential chemotherapeutants to control Aeromonas hydrophila infection in channel catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Using catfish gill cells G1B and four chemicals (hydrogen peroxide, sodium chloride, potassium permanganate, and D-mannose), the feasibility of using an in vitro screening method to identify potential effective chemotherapeutants was evaluated in this study. In vitro screening results revealed that,...

  5. Agent Orange exposure and attributed health effects in Vietnam veterans.

    PubMed

    Young, Alvin L; Cecil, Paul F

    2011-07-01

    Serum dioxin studies of Vietnam (VN) veterans, military historical records of tactical herbicide use in Vietnam, and the compelling evidence of the photodegradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aspects of environmental fate and low bioavailability of TCDD are consistent with few, if any, ground troop veterans being exposed to Agent Orange. That conclusion, however, is contrary to the presumption by the Department of Veterans Affairs (DVA) that military service in Vietnam anytime from January 9, 1962 to May 7, 1975 is a proxy for exposure to Agent Orange. The DVA assumption is inconsistent with the scientific principles governing determinations of disease causation. The DVA has nonetheless awarded Agent Orange-related benefits and compensation to an increasing number of VN veterans based on the presumption of exposure and the published findings of the Institute of Medicine that there is sufficient evidence of a "statistical association" (a less stringent standard than "causal relationship") between exposure to tactical herbicides or TCDD and 15 different human diseases. A fairer and more valid approach for VN veterans would have been to enact a program of "Vietnam experience" benefits for those seriously ill, rather than benefits based on the dubious premise of injuries caused by Agent Orange.

  6. Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species

    PubMed Central

    Liang, Wenquan; Cai, Aizhen; Chen, Guozhu; Xi, Hongqing; Wu, Xiaosong; Cui, Jianxin; Zhang, Kecheng; Zhao, Xudong; Yu, Jiyun; Wei, Bo; Chen, Lin

    2016-01-01

    The prognosis of gastric cancer remains poor due to clinical drug resistance. Novel drugs are urgently needed. Shikonin (SHK), a natural naphthoquinone, has been reported to trigger cell death and overcome drug resistance in anti-tumour therapy. In this study, we investigated the effectiveness and molecular mechanisms of SHK in treatment with gastric cancer. In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells. SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis. We confirmed that SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade, but also in a caspase-independent manner which mediates the nuclear translocation of apoptosis-inducing factor and Endonuclease G. Furthermore, we demonstrated that SHK enhanced the chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin in vitro and in vivo. Taken together, our data show that SHK may be a novel therapeutic agent in the clinical treatment of gastric cancer. PMID:27905569

  7. Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi

    PubMed Central

    Herrera, Linda J.; Brand, Stephen; Santos, Andres; Nohara, Lilian L.; Harrison, Justin; Norcross, Neil R.; Thompson, Stephen; Smith, Victoria; Lema, Carolina; Varela-Ramirez, Armando; Gilbert, Ian H.; Almeida, Igor C.; Maldonado, Rosa A.

    2016-01-01

    Background Trypanosoma cruzi causes Chagas disease, an endemic and debilitating illness in Latin America. Lately, owing to extensive population movements, this neglected tropical disease has become a global health concern. The two clinically available drugs for the chemotherapy of Chagas disease have rather high toxicity and limited efficacy in the chronic phase of the disease, and may induce parasite resistance. The development of new anti-T. cruzi agents is therefore imperative. The enzyme N-myristoyltransferase (NMT) has recently been biochemically characterized, shown to be essential in Leishmania major, Trypanosoma brucei, and T. cruzi¸ and proposed as promising chemotherapeutic target in these trypanosomatids. Methodology/Principal Findings Here, using high-content imaging we assayed eight known trypanosomatid NMT inhibitors, against mammal-dwelling intracellular amastigote and trypomastigote stages and demonstrated that three of them (compounds 1, 5, and 8) have potent anti-proliferative effect at submicromolar concentrations against T. cruzi, with very low toxicity against human epithelial cells. Moreover, metabolic labeling using myristic acid, azide showed a considerable decrease in the myristoylation of proteins in parasites treated with NMT inhibitors, providing evidence of the on-target activity of the inhibitors. Conclusions/Significance Taken together, our data point out to the potential use of NMT inhibitors as anti-T. cruzi chemotherapy. PMID:27128971

  8. Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.

    PubMed Central

    Mangipudy, R S; Rao, P S; Mehendale, H M

    1996-01-01

    In an earlier study we established that timely and adequate tissue repair response following the administration of a six-fold dose-range of thioacetamide (TA; 50, 150, and 300 mg/kg) prevented progression of injury and led to recovery and animal survival. Delayed and attenuated repair response after the 600 mg/kg TA dose resulted in a marked progression of injury and 100% lethality. The objective of the present study was to further scrutinize this concept in an experimental protocol in which we hypothesized that a selective ablation of the tissue repair response should lead to lethality from the nonlethal, moderately toxic doses of 150 and 300 mg/kg TA. In this study we investigated the effect of the antimitotic agent colchicine (CLC, 1 mg/kg) on the outcome of TA hepatotoxicity. Male Sprague-Dawley rats (175-225 g) were injected intraperitoneally (ip) with 150 and 300 mg/kg TA. We assessed liver injury by serum enzyme elevations and histopathology. Tissue regeneration response was measured by 3H-thymidine incorporation into hepatonuclear DNA and by proliferating cell nuclear antigen (PCNA) assay. S-Phase stimulation, as indicated by 3H-thymidine incorporation, was noted at 36 and 48 hr following the administration of 150 mg/kg TA, whereas with the 300 mg/kg TA S-phase stimulation was elicited at 48 hr following treatment. Therefore, two doses of CLC (30 hr and 42 hr, 1 mg/kg, ip) were administered to the 150 mg/kg treated group while a single dose of CLC (42 hr, 1 mg/kg, ip) was administered to the 300 mg/kg group. CLC treatment resulted in 100% lethality in both groups. Thus, CLC administration converted nonlethal doses into lethal doses. The 150 mg/kg TA dose was then chosen to further investigate the underlying mechanism. Rats treated with TA alone recovered from injury by 36-48 hr while CLC treatment resulted in a progression of injury as indicated by serum enzyme elevation and histopathology. Tissue repair, as evidenced by 3H-thymidine incorporation and PCNA

  9. Chemovirotherapy: combining chemotherapeutic treatment with oncolytic virotherapy.

    PubMed

    Binz, Eike; Lauer, Ulrich M

    2015-01-01

    Oncolytic virotherapy has made significant progress in recent years, however, widespread approval of virotherapeutics is still limited. Primarily, this is due to the fact that currently available virotherapeutics are mostly tested in monotherapeutic clinical trials exclusively (ie, not in combination with other therapies) and so far have achieved only small and often clinically insignificant responses. Given that the predominantly immunotherapeutic mechanism of virotherapeutics is somewhat time-dependent and rapidly growing tumors therefore exhibit only minor chances of being captured in time, scenarios with combination partners are postulated to be more effective. Combinatory settings would help to achieve a rapid stabilization or even reduction of onset tumor masses while providing enough time (numerous months) for achieving immuno(viro)therapeutic success. For this reason, combination strategies of virotherapy with highly genotoxic regimens, such as chemotherapy, are of major interest. A number of clinical trials bringing the concepts of chemotherapy and virotherapy together have previously been undertaken, but optimal scheduling of chemovirotherapy (maximizing the anti-tumor effect while minimizing the risk of overlapping toxicity) still constitutes a major challenge. Therefore, an overview of published as well as ongoing Phase I-III trials should improve our understanding of current challenges and future developments in this field.

  10. Tanshinones as Effective Therapeutic Agents for Prostate Cancer

    DTIC Science & Technology

    2011-06-01

    BW) and the routes of administration (oral gavaging with corn oil or dietary supplementation ) in inhibiting the growth of PC-3 tumors. We found...activity against PC3 tumors. Although dietary supplementation was labor-efficient, the intake of the active agents could not be controlled because the...basis for most modern pharmaceutical drugs. Herbal medicines usually contain multiple bioactive compo- nents with specific biological activities and

  11. Chemotherapeutic potential of cow urine: A review

    PubMed Central

    Randhawa, Gurpreet Kaur; Sharma, Rajiv

    2015-01-01

    In the grim scenario where presently about 70% of pathogenic bacteria are resistant to at least one of the drugs for the treatment, cue is to be taken from traditional/indigenous medicine to tackle it urgently. The Indian traditional knowledge emanates from ayurveda, where Bos indicus is placed at a high pedestal for numerous uses of its various products. Urine is one of the products of a cow with many benefits and without toxicity. Various studies have found good antimicrobial activity of cow’s urine (CU) comparable with standard drugs such as ofloxacin, cefpodoxime, and gentamycin, against a vast number of pathogenic bacteria, more so against Gram-positive than negative bacteria. Interestingly antimicrobial activity has also been found against some resistant strains such as multidrug-resistant (MDR) Escherichia coli and Klebsiella pneumoniae. Antimicrobial action is enhanced still further by it being an immune-enhancer and bioenhancer of some antibiotic drugs. Antifungal activity was comparable to amphotericin B. CU also has anthelmintic and antineoplastic action. CU has, in addition, antioxidant properties, and it can prevent the damage to DNA caused by the environmental stress. In the management of infectious diseases, CU can be used alone or as an adjunctive to prevent the development of resistance and enhance the effect of standard antibiotics. PMID:26401404

  12. Strategies for improving chemotherapeutic delivery to solid tumors mediated by vascular permeability modulation

    NASA Astrophysics Data System (ADS)

    Roy Chaudhuri, Tista

    An essential mode of distribution of blood-borne chemotherapeutic agents within a solid tumor is via the micro-circulation. Poor tumor perfusion, because of a lack of functional vasculature or a lack of microvessels, as well as low tumor vascular permeability, can prevent adequate deposition of even low molecular-weight agents into the tumor. The modulation of tumor vascular function and density can provides numerous strategies for improving intratumor deposition of chemotherapeutic agents. Here we investigated strategies to improve drug delivery to two tumor types that share in common poor drug delivery, but differ in the underlying cause. First, in an angiogenesis-driven brain tumor model of Glioblastoma, the vascular permeability barrier, along with poorly-functional vasculature, hinders drug delivery. A strategy of nanoparticle-based tumor 'priming' to attack the vascular permeability barrier, employing sterically stabilized liposomal doxorubicin (SSL-DXR), was investigated. Functional and histological evaluation of tumor vasculature revealed that after an initial period of depressed vascular permeability and vascular pruning 3--4 days after SSL-DXR administration, vascular permeability and perfusion were restored and then elevated after 5--7 days. As a result of tumor priming, deposition of subsequently-administered nanoparticles was enhanced, and the efficacy of temozolomide (TMZ), if administered during the window of elevated permeability, was increased. The sequenced regimen resulted in a persistent reduction of the tumor proliferative index and a 40% suppression of tumor volume, compared to animals that received both agents simultaneously. Second, in a hypovascular, pancreatic ductal adenocarcinoma model, disruption of tumor-stromal communication via sonic hedgehog (sHH) signaling pathway inhibition mediated an indirect vascular proliferation and a more than 2-fold increase in intratumor nanoparticle deposition. Enhanced delivery of SSL-DXR in tumors pre

  13. Effects of Cueing by a Pedagogical Agent in an Instructional Animation: A Cognitive Load Approach

    ERIC Educational Resources Information Center

    Yung, Hsin I.; Paas, Fred

    2015-01-01

    This study investigated the effects of a pedagogical agent that cued relevant information in a story-based instructional animation on the cardiovascular system. Based on cognitive load theory, it was expected that the experimental condition with the pedagogical agent would facilitate students to distinguish between relevant and irrelevant…

  14. Lapse of time effects on tax evasion in an agent-based econophysics model

    NASA Astrophysics Data System (ADS)

    Seibold, Götz; Pickhardt, Michael

    2013-05-01

    We investigate an inhomogeneous Ising model in the context of tax evasion dynamics where different types of agents are parameterized via local temperatures and magnetic fields. In particular, we analyze the impact of lapse of time effects (i.e. backauditing) and endogenously determined penalty rates on tax compliance. Both features contribute to a microfoundation of agent-based econophysics models of tax evasion.

  15. Military chemical warfare agent human subjects testing: part 2--long-term health effects among participants of U.S. military chemical warfare agent testing.

    PubMed

    Brown, Mark

    2009-10-01

    Military chemical warfare agent testing from World War I to 1975 produced thousands of veterans with concerns about how their participation affected their health. A companion article describes the history of these experiments, and how the lack of clinical data hampers evaluation of long-term health consequences. Conversely, much information is available about specific agents tested and their long-term health effects in other populations, which may be invaluable for helping clinicians respond effectively to the health care and other needs of affected veterans. The following review describes tested agents and their known long-term health consequences. Although hundreds of chemicals were tested, they fall into only about a half-dozen pharmaceutical classes, including common pharmaceuticals; anticholinesterase agents including military nerve agents and pesticides; anticholinergic glycolic acid esters such as atropine; acetylcholine reactivators such as 2-PAM; psychoactive compounds including cannabinoids, phencyclidine, and LSD; and irritants including tear gas and riot control agents.

  16. EMOTION RECOGNITION OF VIRTUAL AGENTS FACIAL EXPRESSIONS: THE EFFECTS OF AGE AND EMOTION INTENSITY

    PubMed Central

    Beer, Jenay M.; Fisk, Arthur D.; Rogers, Wendy A.

    2014-01-01

    People make determinations about the social characteristics of an agent (e.g., robot or virtual agent) by interpreting social cues displayed by the agent, such as facial expressions. Although a considerable amount of research has been conducted investigating age-related differences in emotion recognition of human faces (e.g., Sullivan, & Ruffman, 2004), the effect of age on emotion identification of virtual agent facial expressions has been largely unexplored. Age-related differences in emotion recognition of facial expressions are an important factor to consider in the design of agents that may assist older adults in a recreational or healthcare setting. The purpose of the current research was to investigate whether age-related differences in facial emotion recognition can extend to emotion-expressive virtual agents. Younger and older adults performed a recognition task with a virtual agent expressing six basic emotions. Larger age-related differences were expected for virtual agents displaying negative emotions, such as anger, sadness, and fear. In fact, the results indicated that older adults showed a decrease in emotion recognition accuracy for a virtual agent's emotions of anger, fear, and happiness. PMID:25552896

  17. The effects of anesthetic agents on oxidative stress

    NASA Astrophysics Data System (ADS)

    Yakan, Selvinaz; Düzgüner, Vesile

    2016-04-01

    Oxidative stress can be defined as the instability between antioxidant defense of the body and the production of free radical that causes peroxydation on the lipid layer. Free radicals are reactive oxygen species that are produced in the course of normal metabolisms of aerobe organisms and they may cause disorders in cell structure and organelles by interacting macromolecules, like lipid, protein, nucleic acids. Therefore, they may cause cardiovascular, immune system, liver, kidney illnesses and many other illnesses like cancer, aging, cataract, diabetes. It is known that many drugs used for the purpose of anesthetizing may cause lipid peroxidation in organism. For these reasons, determining the Oxidative stress index of anaesthetic stress chosen in the ones that are exposed to long term anaesthetic agents and anaesthesia appliccations, is so substantial.

  18. The effect of coupling agents on composite durability

    SciTech Connect

    Macturk, K.S.; Schultheisz, C.R.; Hunston, D.L.; Schutte, C.L.

    1996-12-31

    The relationship between fiber surface treatments and glass fiber/epoxy composite durability was investigated. The type of silane coupling agent deposited on the fiber surface was varied, and the single fiber fragmentation test was used to measure strengths of the fiber and the fiber-matrix interface. The samples were tested dry and after conditioned in 75{degrees}C distilled water for up to 10 weeks. With dry samples the interface strengths varied with the reactivity of the silane deposited on the surface. Moisture exposure produced little change in fiber strengths and, for samples containing silane treated fibers, little change in interface strength, even when the silane was unreactive with the epoxy. In contrast, samples containing unsized fibers exhibited significant losses in interface strengths.

  19. Biomarker-Guided Repurposing of Chemotherapeutic Drugs for Cancer Therapy: A Novel Strategy in Drug Development

    PubMed Central

    Stenvang, Jan; Kümler, Iben; Nygård, Sune Boris; Smith, David Hersi; Nielsen, Dorte; Brünner, Nils; Moreira, José M. A.

    2013-01-01

    Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point. PMID:24400218

  20. Effects of antithrombotic agents evaluated in a nonhuman primate vascular shunt model.

    PubMed Central

    Mason, R. G.; Wolf, R. H.; Zucker, W. H.; Shinoda, B. A.; Mohammad, S. F.

    1976-01-01

    The effects of aspirin, cyproheptadine, dextran, dipyridamole, and sulfinpyrazone on thrombus deposition were determined. These antithrombotic agents were evaluated in a nonhuman primate model for thrombus generation that employed test devices exposed to blood in an arteriovenous shunt. Thrombus deposition on test devices was quantitated gravimetrically. Of the antithrombotic agents tested, cyproheptadine was found to be the most effective, and aspirin, dextran, and dipyridamole were each somewhat less effective. Sulfinpyrazone had only a slight antithrombotic effect. Ultrastructual studies of thrombus deposited in test devices showed that the various antithrombotic agents tested did not prevent completely the formation of fibrin, aggregation of platelets, or adhesion and spreading of platelets and leukocytes. This model for thrombus generation is felt to be a more efficient means for evaluating antithrombotic agents than previously described nonhuman primate models. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:820202

  1. Identification of Aminopyridazine-Derived Antineuroinflammatory Agents Effective in an Alzheimer's Mouse Model

    PubMed Central

    2012-01-01

    Targeting neuroinflammation may be a new strategy to combat Alzheimer's disease. An aminopyridazine 1b previously reported as a novel antineuroinflammatory agent was considered to have a potential therapeutic effect for Alzheimer's disease. In this study, we further explored the chemical space to identify more potent antineuroinflammatory agents and validate their in vivo efficacy in an animal model. Compound 14 was finally identified as an effective agent with comparable in vivo efficacy to the marketed drug donepezil in counteracting spatial learning and working memory impairment in an Aβ-induced Alzheimer's mouse model. PMID:24900405

  2. The Effect of Information Level on Human-Agent Interaction for Route Planning

    DTIC Science & Technology

    2015-12-01

    more time may not necessarily mean an “ overload ” of information . All participants in both experiments successfully met their performance goal of...ARL-TR-7563 ● DEC 2015 US Army Research Laboratory The Effect of Information Level on Human-Agent Interaction for Route Planning...Army Research Laboratory The Effect of Information Level on Human-Agent Interaction for Route Planning by Julia L Wright, Michael W Boyce

  3. MnO2-Based Nanoplatform Serves as Drug Vehicle and MRI Contrast Agent for Cancer Theranostics.

    PubMed

    Zhang, Mei; Xing, Lei; Ke, Hengte; He, Yu-Jing; Cui, Peng-Fei; Zhu, Yong; Jiang, Ge; Qiao, Jian-Bin; Lu, Na; Chen, Huabing; Jiang, Hu-Lin

    2017-04-05

    Multidrug resistance (MDR) greatly impedes the therapeutic efficacy of chemotherapeutic agents. Overexpression of ATP-binding cassette (ABC) transporters, such as P-gp, on the surface of tumor cells is a major mechanism in MDR. In this study, we fabricated manganese dioxide (MnO2)/doxorubicin (DOX)-loaded albumin nanoparticles (BMDN) for magnetic resonance imaging and reversing MDR in resistant tumor. BMDN facilitated the delivery of DOX into MDR tumor cells through their MDR reversal effects including enhanced cellular uptake, reduced drug efflux, and decreased hypoxic tumor microenvironment. BMDN also acted as an effective MRI contrast agent, thereby causing good in vitro and in vivo T1-weighted imaging.

  4. Comparative study of the effects of two bleaching agents on oral microbiota.

    PubMed

    Alkmin, Yara Tardelli; Sartorelli, Renata; Flório, Flávia Martão; Basting, Roberta Tarkany

    2005-01-01

    This study evaluated the in vivo effects of bleaching agents containing 10% carbamide peroxide (Platinum/Colgate) or 7.5% hydrogen peroxide (Day White 2Z/Discus Dental) on mutans Streptococcus during dental bleaching. The products were applied on 30 volunteers who needed dental bleaching. In each volunteer, one of the two bleaching agents was used on both dental arches one hour a day for three weeks. Analysis of the bacterial counts was made by collecting saliva before (baseline values), during (7 and 21 days) bleaching treatments and 14 days posttreatment. The Friedman non-parametric analysis (alpha=0.05) found no differences in microorganism counts at different times for each group for both agents (p>0.05). The Mann Whitney nonparametric test (alpha=0.05) showed no differences in micro-organism counts for both agents (p>0.05). Different bleaching agents did not change the oral cavity mutans Streptococcus counts.

  5. [Effects of sunscreening agents and reactions with ultraviolet radiation].

    PubMed

    Bredholt, K; Christensen, T; Hannevik, M; Johnsen, B; Seim, J; Reitan, J B

    1998-06-30

    The use of sunscreens is extensive. During the last few years there have been indications that UV radiation causes breakdown of the sunlight absorbing filters in the sunscreens, i.e. the sunscreens are not photostable. We describe briefly UV propagation in skin, the chemical and physical properties of sunscreens, and how these may react during UV irradiation. We have studied the stability of several sunscreens in vitro. The stability tests were performed by applying a thin film of the sunscreen preparation to the wall of a quartz window, irradiating it with a sun simulator, and measuring the absorbance with spectrophotometry before and during irradiation. The sunscreen agent studied most thoroughly was the UVB filter octyl methoxy cinnamate, but other UVA and UVB filters and some commercial products were also tested. Considerable breakdown of most filters was observed after doses of irradiation equivalent to moderate sun exposure. It can be questioned whether the breakdown products of sunscreens also possess other physical or biological properties. General practitioners should be able to advise their patients on sun protection and the proper use of sunscreens, considering the extensive use of sunscreens and the fact that sunbathing may be a health hazard.

  6. The effects of anti-inflammatory agents on skin tumor initiation and aryl hydrocarbon hydroxylase.

    PubMed

    Slaga, T J; Viaje, A; Bracken, W

    1977-02-01

    The effects of various clinically used anti-inflammatory agents on mouse skin tumorigenesis and aryl hydrocarbon hydroxylase (AHH) were investigated. Oxyphenbutazone, a nonsteroidal anti-inflammatory agent, inhibited 3-methylcholanthrene (MC) tumor initiation but was less effective than the steroidal anti-inflammatory agent, dexamethasone. Oxyphenbutazone was not found to induce AHH activity in mouse epidermis, whereas indomethacin and Seclazone had a slight inducing effect. When these agents were added directly to the in vitro AHH assay, they did not inhibit AHH activity. However, additional experiments have shown a decreased epidermally mediated covalent binding of MC to DNA in vitro when the epidermal homogenates were isolated from mice pretreated with either dexamethasone or oxyphenbutazone and MC at 3 or 12 hr before killing.

  7. Obtaining rapid and effective hemostasis: Part I. Update and review of topical hemostatic agents.

    PubMed

    Howe, Nicole; Cherpelis, Basil

    2013-11-01

    Effective and rapid hemostasis is critical to optimize surgical outcomes. An advantageous adjunct in accelerating the clotting process during dermatologic surgery is the use of topical hemostatic agents, which allow dermatologic surgeons to quickly clear the surgical field while avoiding the adverse effects of systemic medications. The growing rate of patients with pacemakers and defibrillators limits the possibility of electrosurgery. It is not unusual for patients to be taking ≥1 anticoagulant medication(s). For these reasons, the use of topical hemostatic agents is likely to gain more recognition in the literature. The term topical hemostatic agents encompasses an array of pharmacotherapies, sealants, adhesives, absorbable agents, biologics, and combination products. The optimal use of topical hemostatic agents demands that dermatologic surgeons be familiar with each of these options, because the type of product used must be selected based on surgical location, wound size, and the extent of bleeding. With few randomized controlled trials in existence reviewing the efficacy of these medications, the subject of topical styptic agents has largely gone unstudied. Part I of this continuing medical education article reviews the available topical hemostatic agents and the ideal clinical settings for their use.

  8. Emergent Societal Effects of Crimino-Social Forces in an Animat Agent Model

    NASA Astrophysics Data System (ADS)

    Scogings, Chris J.; Hawick, Ken A.

    Societal behaviour can be studied at a causal level by perturbing a stable multi-agent model with new microscopic behaviours and observing the statistical response over an ensemble of simulated model systems. We report on the effects of introducing criminal and law-enforcing behaviours into a large scale animat agent model and describe the complex spatial agent patterns and population changes that result. Our well-established predator-prey substrate model provides a background framework against which these new microscopic behaviours can be trialled and investigated. We describe some quantitative results and some surprising conclusions concerning the overall societal health when individually anti-social behaviour is introduced.

  9. The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents

    PubMed Central

    Petschauer, Jennifer S.; Madden, Andrew J.; Kirschbrown, Whitney P.; Song, Gina; Zamboni, William C.

    2015-01-01

    Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients. PMID:25707978

  10. Effects of hydrogen peroxide-containing bleaching agents on the morphology of human enamel.

    PubMed

    Ernst, C P; Marroquín, B B; Willershausen-Zönnchen, B

    1996-01-01

    The effects of four bleaching agents (Opalescence, HiLite, 30% hydrogen peroxide, and 30% hydrogen peroxide mixed with sodium perborate) and 37% phosphoric acid on the external surface of human enamel were examined with the scanning electron microscope. The materials were applied to the enamel surfaces of 60 specimens obtained from 10 teeth. Each test agent was applied to one specimen from each tooth. One specimen of each tooth was left untreated. Comparison to the untreated control surfaces revealed that enamel exposed to the bleaching agents underwent slight morphologic surface alterations. The enamel surfaces treated with phosphoric acid, in contrast, showed severe morphologic alterations.

  11. Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

    PubMed Central

    2015-01-01

    Early–late transition metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh2}AuCl] (R = −CH2– 6, −4-C6H4– 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC503 = 91 nM, IC505 = 117 nM). The selectivity of the compounds in vitro against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially 5) are excellent candidates for further development as potential renal cancer chemotherapeutics. PMID:25435644

  12. Low molecular weight chitosan is an effective antifungal agent against Botryosphaeria sp. and preservative agent for pear (Pyrus) fruits.

    PubMed

    Wang, Yunguang; Li, Bin; Zhang, Xuedan; Peng, Nan; Mei, Yuxia; Liang, Yunxiang

    2017-02-01

    Antifungal activity and preservative effect of a low molecular weight chitosan (LMWC) sample, derived from chitosan by enzymatic hydrolysis, were investigated in vitro and in vivo. A pathogenic fungal strain was isolated from decayed pear (Pyrus bretschneideri cv. "Huangguan") fruit and identified as Botryosphaeria sp. W-01. LMWC was shown to strongly inhibit W-01 growth based on studies of minimum inhibitory concentration (MIC) and effects on mycelial biomass and radial growth of the fungus. LMWC treatment of W-01 cells reduced ergosterol synthesis and mitochondrial membrane potential (ΔY), early events of apoptosis. Transmission electron microscopy and confocal laser scanning microscopy studies revealed that LMWC penetrated inside W-01 hyphae, thereby inducing ultrastructural damage. LMWC coating had a significant preservative effect on wounded and nonwounded pear fruits, by inhibiting postharvest decay and browning processes. LMWC activated several defense-related enzymes (polyphenol oxidase, peroxidase, chitinase), maintained nutritional value, and slowed down weight loss. Our findings indicate the strong potential of LMWC as a natural preservative agent for fruits and vegetables.

  13. Effects of coloring agents applied during sintering on bending strength and hardness of zirconia ceramics.

    PubMed

    Kuroda, Soichi; Shinya, Akikazu; Yokoyama, Daiichiro; Gomi, Harunori; Shinya, Akiyoshi

    2013-01-01

    The effects of coloring agents (Vita in-ceram 2000 YZ coloring liquid (VL) and IPS e.max ZirCAD (IS)) and shades (1, 3, and 5) applied during sintering on the bending strength and fracture toughness of zirconia ceramics was examined. No differences in the bending strength or fracture toughness were observed for the type of coloring agent used. Moreover, the bending strength and Vickers hardness of the zirconia ceramics decreased, while the crack length and fracture toughness did not change with the different coloring agents. The marginal borders of the indentations formed were clear and linear, and no damage, including chipping, was observed. Therefore, clinical application of zirconia ceramics can be recommended because the coloring agents and shades applied during sintering have the same effect as an opaque layer and cause no significant deterioration of the mechanical properties of the zirconia ceramics.

  14. Vanadium Compounds as Pro-Inflammatory Agents: Effects on Cyclooxygenases

    PubMed Central

    Korbecki, Jan; Baranowska-Bosiacka, Irena; Gutowska, Izabela; Chlubek, Dariusz

    2015-01-01

    This paper discusses how the activity and expression of cyclooxygenases are influenced by vanadium compounds at anticancer concentrations and recorded in inorganic vanadium poisonings. We refer mainly to the effects of vanadate (orthovanadate), vanadyl and pervanadate ions; the main focus is placed on their impact on intracellular signaling. We describe the exact mechanism of the effect of vanadium compounds on protein tyrosine phosphatases (PTP), epidermal growth factor receptor (EGFR), PLCγ, Src, mitogen-activated protein kinase (MAPK) cascades, transcription factor NF-κB, the effect on the proteolysis of COX-2 and the activity of cPLA2. For a better understanding of these processes, a lot of space is devoted to the transformation of vanadium compounds within the cell and the molecular influence on the direct targets of the discussed vanadium compounds. PMID:26053397

  15. Radiofrequency hyperthermia promotes the therapeutic effects on chemotherapeutic-resistant breast cancer when combined with heat shock protein promoter-controlled HSV-TK gene therapy: Toward imaging-guided interventional gene therapy

    PubMed Central

    Luo, Jingfeng; Wu, Xiaotian; Zhou, Fei; Zhou, Yurong; Huang, Tongchun; Liu, Fei; Han, Guocan; Chen, Luming; Bai, Weixian; Wu, Xia; Sun, Jihong; Yang, Xiaoming

    2016-01-01

    Objective Gene therapy is a frontier in modern medicine. In the present study, we explored a new technique for the effective treatment of multidrug-resistant (MDR) breast cancer by combining fully the advantages of multidisciplinary fields, including image-guided minimally invasive interventional oncology, radiofrequency technology, and direct intratumoral gene therapy. Results Combination treatment with PHSP-TK plus RFH resulted in significantly higher TK gene transfection/expression, as well as a lower cell proliferation rate and a higher cell apoptosis index, than those of control groups. In vivo validation experiments with MRI confirmed that combination therapy resulted in a significant reduction of relative tumor volume compared with those of control animals, which was supported by the results of histologic and apoptosis analyses. Materials and methods The heat shock protein promoter (PHSP) was used to precisely control the overexpression of thymidine kinase (TK) (PHSP-TK). Serial in vitro experiments were performed to confirm whether radiofrequency hyperthermia (RFH) could enhance PHSP-TK transfection and expression in a MDR breast cancer cell line (MCF7/Adr). Serial in vivo experiments were then carried out to validate the feasibility of the new technique, termed interventional RFH-enhanced direct intratumoral PHSP-TK gene therapy. The therapeutic effect of combination therapy was evaluated by MRI and confirmed by subsequent laboratory correlation. Conclusions This study has established “proof-of-principle” of a new technique, interventional RFH-enhanced local gene therapy for MDR breast cancer, which may open new avenues for the effective management of MDR breast cancers via the simultaneous integration of interventional oncology, RF technology, and direct intratumoral gene therapy. PMID:27542255

  16. [Bi-weekly nab-paclitaxel and trastuzumab therapy effective against recurrent breast cancer with multiple lung metastases in elderly patient who had previously undergone two chemotherapeutic regimens for treatment of metastatic disease-a case Report].

    PubMed

    Sakurai, Teruhisa; Jinta, Eri; Suzuma, Takaomi; Yoshimura, Gorou; Umemura, Teiji; Sakurai, Takeo

    2012-11-01

    We herein report a 75-year-old patient with recurrent hormone-nonresponsive, HER2-positive breast cancer who presented with multiple lung metastases. She had undergone a mastectomy followed by adjuvant chemotherapy with FEC, CMF, and UFT. Forty-six months after the surgery, multiple lung, liver, and bone metastases were observed. Docetaxel and trastuzumab were administered as first-line chemotherapy for 13 months. A partial response and stable disease were observed, but progressive disease in the lung and brain was subsequently revealed. The patient then underwent g-knife treatment for brain metastasis. Lapatinib and capecitabine treatment was administered as second-line chemotherapy for 9 months. Stable disease was observed, but progressive disease in the lung metastases with clinical symptoms including cough, exertional dyspnea, and general malaise was revealed. As third-line chemotherapy, the patient was administered low-dose, bi-weekly nab-paclitaxel(150mg/m2)and trastuzumab therapy. Four weeks after beginning the nab-paclitaxel and trastuzumab treatment, the cough disappeared; 2 months after beginning the therapy, a partialresponse in the lung metastases was seen. The patient is well and the treatment has been continued for 50 weeks. No progression has been seen. Bi-weekly nab-paclitaxel treatment appears to have few side effects and might be an effective treatment option for patients with recurrent breast cancer.

  17. Effects of Tooth Coating Material and Finishing Agent on Bleached Enamel Surfaces by KTP Laser

    PubMed Central

    Kameda, Ayumi; Masuda, Yoshiko Murakami; Teruo, Toko; Yamada, Yoshishige; Kimura, Yuichi; Tamaki, Yukimichi; Miyazaki, Takashi

    2013-01-01

    Objective: The purpose of this study was to evaluate the effect of tooth coating material and finishing agent on bleached enamel surfaces after using KTP laser with 27% hydrogen peroxide. Background data: There have been few reports on the effects of tooth coating materials and finishing agents after bleaching. Methods: After 40 crowns of human extracted maxillary incisors were bleached by KTP laser, bleached enamels were finished with fluoride only or both of fluoride and nano-hydroxyapatite as a finishing agent. After application(s) of fluoride and/or finishing agent, the enamel surfaces were divided into 2 groups, which were covered with the coating material or without coating material. After application of coating materials, all specimens were kept for 2 weeks at 37°C of 100% humidity. After removing the coating material, color changing was measured and enamel surfaces were examined by scanning electron microscopy (SEM). Results: SEM observation of enamel surfaces treated the fluoride gel, finishing agent and coating material showed the most flattered surface compared to other groups. By measuring the color changing, few color changing was observed on the enamel surfaces treated the fluoride gel, finishing agents and coating material. Conclusion: These results suggested that applications of fluoride gel, finishing agent and coating material made the enamel-surfaces flattered and kept effects of bleaching, could prevent the re-coloration. After applications of fluoride gel and finishing agent, covering the bleached-enamel surfaces with the coating material enhanced the keeping whiteness. It would give the patients satisfaction of whiteness. PMID:24155557

  18. Comparison of Cantharidin Toxicity in Breast Cancer Cells to Two Common Chemotherapeutics

    PubMed Central

    Kern, Katie M.; Schroeder, Jennifer R.

    2014-01-01

    As part of a larger study synthesizing a more directed form of chemotherapy, we have begun to assess the efficacy of different potential toxins that could be delivered locally rather than systemically. In doing so, we hope to reduce the systemic side effects commonly observed, while maintaining a high level of toxicity and eliminating the need for metabolic alterations. In a search for this more efficient method for killing cancerous cells, we have begun studying cantharidin, a toxin used in traditional Chinese medicine, as a potential chemotherapeutic. Using an MTT cell viability assay, the toxicity of cantharidin was compared to both cyclophosphamide and paclitaxel in three different breast cancer cell lines: MCF-7, MDA-MB-231, and SK-BR-3. Increasing the concentration of chemotherapy drugs did decrease cell viability in all cell lines when cantharidin and cyclophosphamide were applied; however differences for paclitaxel were cell-specific. Additionally, cantharidin exhibited the highest decrease in cell viability regardless of cell type, indicating it may be a much more potent and less specific chemotherapeutic. These results will help us move forward in developing a potentially more potent treatment for breast cancer that might eliminate the need for subtype-specific treatments. PMID:25302124

  19. Molecular effective coverage surface area of optical clearing agents for predicting optical clearing potential

    NASA Astrophysics Data System (ADS)

    Feng, Wei; Ma, Ning; Zhu, Dan

    2015-03-01

    The improvement of methods for optical clearing agent prediction exerts an important impact on tissue optical clearing technique. The molecular dynamic simulation is one of the most convincing and simplest approaches to predict the optical clearing potential of agents by analyzing the hydrogen bonds, hydrogen bridges and hydrogen bridges type forming between agents and collagen. However, the above analysis methods still suffer from some problem such as analysis of cyclic molecule by reason of molecular conformation. In this study, a molecular effective coverage surface area based on the molecular dynamic simulation was proposed to predict the potential of optical clearing agents. Several typical cyclic molecules, fructose, glucose and chain molecules, sorbitol, xylitol were analyzed by calculating their molecular effective coverage surface area, hydrogen bonds, hydrogen bridges and hydrogen bridges type, respectively. In order to verify this analysis methods, in vitro skin samples optical clearing efficacy were measured after 25 min immersing in the solutions, fructose, glucose, sorbitol and xylitol at concentration of 3.5 M using 1951 USAF resolution test target. The experimental results show accordance with prediction of molecular effective coverage surface area. Further to compare molecular effective coverage surface area with other parameters, it can show that molecular effective coverage surface area has a better performance in predicting OCP of agents.

  20. Comparative effects of chelating agents on distribution, excretion, and renal toxicity of inorganic mercury in rats

    SciTech Connect

    Kojima, S.; Shimada, H.; Kiyozumi, M. )

    1989-06-01

    The effects of three chelating agents, sodium N-benzyl-D-glucamine dithiocarbamate(NBG-DTC), 2,3-dimercaptopropanol(BAL), and D-penicillamine(D-PEN), on the distribution, excretion, and renal toxicity of inorganic mercury were compared in rats exposed to HgCl2. Rats were injected i.p. with 203HgCl2 (300 micrograms of Hg and 2 microCi of 203Hg/kg) and 30 min or 24 h later they were injected with a chelating agent (a quarter of an LD50). The injection of the chelating agents significantly enhanced the biliary and urinary excretions of mercury. BAL was the most effective for removal of mercury from the body at 30 min after mercury treatment. The extent of enhancing effect of the chelating agents for removal of mercury at 24 h after mercury was in the order NBG-DTC = BAL greater than D-PEN. The injection of BAL at 24 h after mercury treatment caused the redistribution of mercury to the heart and lung. NBG-DTC did not result in the redistribution of mercury to the heart, lung, and brain. Urinary excretion of protein and AST significantly increased 24-48 h after mercury treatment and decreased to the control values 72 h after mercury. The injection of the chelating agents at 30 min after mercury treatment significantly decreased the urinary excretion of protein and AST. In rats pretreated with mercury 24 h earlier, the chelating agents significantly decreased the urinary protein at 48 h after mercury treatment, but did not decrease the urinary AST. The results of this study indicate that the chelating agents are effective in removing mercury from the body, resulting in the protective effect against the mercury-induced renal damage.

  1. Effect of Atmospheric Background Aerosols on Biological Agent Detectors

    DTIC Science & Technology

    2007-06-01

    Advanced Research Projects Agency, DARPA Chemical and Biological Sensor Standards Study. 32 Massachusetts Institute of Technology (MIT) Laboratory, JBPDS...the Research Program on BW Detection, Space General, AD480357, 1966. (U) The goal of this project was to examine the effects of background...that relied on detection of chemiluminescence resulting from a chemical reaction UNCLASSIFIED 8 UNCLASSIFIED with luminal and porphyrin4. During

  2. Early effects of the antineoplastic agent salinomycin on mitochondrial function.

    PubMed

    Managò, A; Leanza, L; Carraretto, L; Sassi, N; Grancara, S; Quintana-Cabrera, R; Trimarco, V; Toninello, A; Scorrano, L; Trentin, L; Semenzato, G; Gulbins, E; Zoratti, M; Szabò, I

    2015-10-22

    Salinomycin, isolated from Streptomyces albus, displays antimicrobial activity. Recently, a large-scale screening approach identified salinomycin and nigericin as selective apoptosis inducers of cancer stem cells. Growing evidence suggests that salinomycin is able to kill different types of non-stem tumor cells that usually display resistance to common therapeutic approaches, but the mechanism of action of this molecule is still poorly understood. Since salinomycin has been suggested to act as a K(+) ionophore, we explored its impact on mitochondrial bioenergetic performance at an early time point following drug application. In contrast to the K(+) ionophore valinomycin, salinomycin induced a rapid hyperpolarization. In addition, mitochondrial matrix acidification and a significant decrease of respiration were observed in intact mouse embryonic fibroblasts (MEFs) and in cancer stem cell-like HMLE cells within tens of minutes, while increased production of reactive oxygen species was not detected. By comparing the chemical structures and cellular effects of this drug with those of valinomycin (K(+) ionophore) and nigericin (K(+)/H(+) exchanger), we conclude that salinomycin mediates K(+)/H(+) exchange across the inner mitochondrial membrane. Compatible with its direct modulation of mitochondrial function, salinomycin was able to induce cell death also in Bax/Bak-less double-knockout MEF cells. Since at the concentration range used in most studies (around 10 μM) salinomycin exerts its effect at the level of mitochondria and alters bioenergetic performance, the specificity of its action on pathologic B cells isolated from patients with chronic lymphocytic leukemia (CLL) versus B cells from healthy subjects was investigated. Mesenchymal stromal cells (MSCs), proposed to mimic the tumor environment, attenuated the apoptotic effect of salinomycin on B-CLL cells. Apoptosis occurred to a significant extent in healthy B cells as well as in MSCs and human primary

  3. [Toxicological effects of weapons of mass destruction and noxious agents in modern warfare and terrorism].

    PubMed

    Vucemilović, Ante

    2010-06-01

    Weapons of mass destruction (WMD) best portray the twisted use of technological achievements against the human species. Despite arm control efforts, WMD threat continues to exist and even proliferate. This in turn calls for improvement in defensive measures against this threat. The modern soldier is exposed to a number of chemical, biological, and radiological agents in military and peace operations, while civilians are mainly exposed to terrorist attacks. Regardless of origin or mode of action, WMDs and other noxious agents aim for the same - to make an organism dysfunctional. Because their effects are often delayed, these agents are hard to spot on time and treat. This review presents a biomedical aspect of agents used in warfare and terrorism, including polonium-210, depleted uranium, salmonella, anthrax, genetically modified bacteria, cobweb-like polymer fibre, sarin, and mustard gas.

  4. Activation of Aluminum as an Effective Reducing Agent by Pitting Corrosion for Wet-chemical Synthesis

    PubMed Central

    Li, Wei; Cochell, Thomas; Manthiram, Arumugam

    2013-01-01

    Metallic aluminum (Al) is of interest as a reducing agent because of its low standard reduction potential. However, its surface is invariably covered with a dense aluminum oxide film, which prevents its effective use as a reducing agent in wet-chemical synthesis. Pitting corrosion, known as an undesired reaction destroying Al and is enhanced by anions such as F−, Cl−, and Br− in aqueous solutions, is applied here for the first time to activate Al as a reducing agent for wet-chemical synthesis of a diverse array of metals and alloys. Specifically, we demonstrate the synthesis of highly dispersed palladium nanoparticles on carbon black with stabilizers and the intermetallic Cu2Sb/C, which are promising candidates, respectively, for fuel cell catalysts and lithium-ion battery anodes. Atomic hydrogen, an intermediate during the pitting corrosion of Al in protonic solvents (e.g., water and ethylene glycol), is validated as the actual reducing agent. PMID:23390579

  5. Effects of modifying agents on surface modifications of magnesium oxide whiskers

    NASA Astrophysics Data System (ADS)

    Zhao, Yun; Liu, Bei; Yang, Jinjun; Jia, Junping; You, Chen; Chen, Minfang

    2016-12-01

    In this work, the MgO whiskers have been treated by several modifying agents including the mixture of DL-malic acid oligo-L-lactide (g), aluminate coupling agent (Al) and stearic acid (Sa). The morphologies, covering quantity, compositions and components of the whiskers before and after the modifications were investigated by SEM, TG, XRD and FT-IR, respectively. Comparisons have been made on the morphologies of modified whiskers by different modifiers tailoring. The results show that the MgO whiskers treated by stearic acid have superior performance to the others, especially in terms of uniform dispersion. In contrast, both the mixture of DL-malic acid oligo-L-lactide and aluminate coupling agent have the negative effects on whiskers' dispersibility. FT-IR reveals that the chemical bonds were formed between the whiskers and each modifying agent and the XRD testing demonstrate that the crystal structures of the modified whiskers were well maintained without significant change.

  6. Endothelial function impairment in chronic venous insufficiency: effect of some cardiovascular protectant agents.

    PubMed

    Carrasco, Omar F; Ranero, Alejandra; Hong, Enrique; Vidrio, Horacio

    In segments of human varicose veins, endothelial function was assessed by measuring relaxation induced by acetylcholine in noradrenaline-precontracted preparations. In addition, concentration-response curves to acetylcholine were obtained before and after incubation with the arterial endothelium protectant agents captopril, losartan, troglitazone, pravastatin, or simvastatin. The antivaricose agent escin was also tested. Mean acetylcholine-induced relaxation of varicose venous rings was about 13%, approximately one third of that reported for control saphenous veins. Concentration-response curves to acetylcholine were ''u'' shaped, the result of endothelium-mediated relaxation at low concentrations, superseded by subsequent smooth muscle contractile responses. Relaxation was enhanced by the endothelium-protecting agents and by escin, troglitazone being the least, and simvastatin the most effective. It was concluded that endothelial dysfunction is present in varicose veins, that this anomaly can be reverted by cardiovascular protecting agents, and that it can play a role in the pathogenesis and treatment of chronic venous insufficiency.

  7. Effects of surface active agents on DNAPL migration and distribution in saturated porous media.

    PubMed

    Cheng, Zhou; Gao, Bin; Xu, Hongxia; Sun, Yuanyuan; Shi, Xiaoqing; Wu, Jichun

    2016-11-15

    Dissolved surface active agents such as surfactant and natural organic matter can affect the distribution and fate of dense nonaqueous liquids (DNAPLs) in soil and groundwater systems. This work investigated how two common groundwater surface active agents, humic acid (HA) and Tween 80, affected tetrachloroethylene (PCE) migration and source zone architecture in saturated porous media under environmentally relevant conditions. Batch experiments were first conducted to measure the contact angles and interfacial tensions (IFT) between PCE and quartz surface in water containing different amount of surface active agents. Results showed that the contact angle increased and IFT decreased with concentration of surface active agent increasing, and Tween 80 was much more effective than HA. Five 2-D flow cell experiments were then conducted. Correspondingly, Tween 80 showed strong effects on the migration and distribution of PCE in the porous media due to its ability to change the medium wettability from water-wet into intermediate/NAPL-wet. The downward migration velocities of the PCE in three Tween 80 cells were slower than those in the other two cells. In addition, the final saturation of the PCE in the cells containing surface active agents was higher than that in the water-only cell. Results from this work indicate that the presence of surface active agents in groundwater may strongly affect the fate and distribution of DNAPL through altering porous medium wettability.

  8. Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property.

    PubMed

    Azmi, Asfar S; Sarkar, Fazlul H; Hadi, S M

    2013-01-01

    " Let food be thy medicine and medicine be thy food" was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents.

  9. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure?

    PubMed

    Apetoh, L; Ladoire, S; Coukos, G; Ghiringhelli, F

    2015-09-01

    Recent clinical trials revealed the impressive efficacy of immunological checkpoint blockade in different types of metastatic cancers. Such data underscore that immunotherapy is one of the most promising strategies for cancer treatment. In addition, preclinical studies provide evidence that some cytotoxic drugs have the ability to stimulate the immune system, resulting in anti-tumor immune responses that contribute to clinical efficacy of these agents. These observations raise the hypothesis that the next step for cancer treatment is the combination of cytotoxic agents and immunotherapies. The present review aims to summarize the immune-mediated effects of chemotherapeutic agents and their clinical relevance, the biological and clinical features of immune checkpoint blockers and finally, the preclinical and clinical rationale for novel therapeutic strategies combining anticancer agents and immune checkpoint blockers.

  10. Effect of New Antiviral Agent Camphecin on Behavior of Mice.

    PubMed

    Babina, A V; Lavrinenko, V A; Yarovaya, O I; Salakhutdinov, N F

    2017-01-01

    We studied the effect of camphecin (1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol) on mouse behavior in the open-field test. Camphecin possesses antiviral activity and inhibits viral replication, but its influence on the nervous system is poorly studied. Single camphecin injection produced no significant changes in behavioral patterns. Chronic camphecin administration (5 times over 2 weeks) to mice of different strains had no significant influence on open field behavior (motor, exploratory activity, anxiety, emotional state and vegetative functions). The findings are discussed in the context of neutral influence of camphecin on animal behavior.

  11. Effects of nonlinear propagation in ultrasound contrast agent imaging.

    PubMed

    Tang, Meng-Xing; Kamiyama, Naohisa; Eckersley, Robert J

    2010-03-01

    This paper investigates two types of nonlinear propagation and their effects on image intensity and contrast-to-tissue ratio (CTR) in contrast ultrasound images. Previous studies have shown that nonlinear propagation can occur when ultrasound travels through tissue and microbubble clouds, making tissue farther down the acoustic path appear brighter in pulse inversion (PI) images, thus reducing CTR. In this study, the effect of nonlinear propagation through tissue or microbubbles on PI image intensity and CTR are compared at low mechanical index. A combination of simulation and experiment with SonoVue microbubbles were performed using a microbubble dynamics model, a laboratory ultrasound system and a clinical prototype scanner. The results show that, close to the bubble resonance frequency, nonlinear propagation through a bubble cloud of a few centimeter thickness with a modest concentration (1:10000 dilution of SonoVue microbubbles) is much more significant than through tissue-mimicking material. Consequently, CTR in regions distal to the imaging probe is greatly reduced for nonlinear propagation through the bubble cloud, with as much as a 12-dB reduction compared with nonlinear propagation through tissue-mimicking material. Both types of nonlinear propagation cause only a small change in bubble PI signals at the bubble resonance frequency. When the driving frequency increases beyond bubble resonance, nonlinear propagation through bubbles is greatly reduced in absolute values. However because of a greater reduction in nonlinear scattering from bubbles at higher frequencies, the corresponding CTR is much lower than that at bubble resonance frequency.

  12. Effects of orally administered chemotherapeutics (quinine, salinomycin) against Henneguya sp. Thelohán, 1892 (Myxozoa: Myxobolidae), a gill parasite in the tapir fish Gnathonemus petersii Günther, 1862 (Teleostei).

    PubMed

    Dohle, Angelika; Schmahl, Günter; Raether, Wolfgang; Schmidt, Hartmut; Ritter, Günter

    2002-09-01

    When given orally, quinine or salinomycin cause irreversible damage to the plasmodial developmental stages of Henneguya sp., a gill parasite in the tapir fish Gnathonemus petersii. Naturally infected tapir fish measured 75-169 mm in total length and their total weight ranged over 4.3-11.7 g. The fish bore 7-77 plasmodia in their gill arches. Medicinal food containing either quinine (5 g/1000 g food) or salinomycin (0.075 g/1000 g food) was given once a day to naturally infected fish in a food chain via water fleas ( Daphnia spp) for a period of 3, 6, or 9 days. From the monitored feeding of the tapir fish and weight determinations of the water fleas, it was calculated that gross uptake was 18.5 micro g/kg body weight fish daily for pure salinomycin and was 1.25 mg/kg body weight daily for quinine. After the end of the experiments, the fish were sacrificed and the plasmodia were carefully prepared from the gill arches and processed for transmission electron microscopy. As seen by ultrastructure investigations, for both substances the grade of damage in the parasites correlated positively with the period of application. When quinine was given for a 3-day period, the trophozoite ecto- and endoplasm exerted numerous vacuoles, caused by the drug, and the presporogonous and the pansporoblastic stages were malformed. Following a 6-day period, numerous abortive polar capsules were found in the trophozoite cytoplasm. To a large extent, the limiting membranes of the polaroblasts and valvogenic cells were destroyed. In addition, deep clefts between the polaroblasts, the valvogenic cells and between the two sporoblasts were observed. Following a 9-day treatment, all damage increased and, in addition, generative cells and two-cell stages were no longer detectable. As a first sign for the effects of salinomycin, following a 3-day treatment, a shrinking of the whole plasmodia occurred and the sutures in the pansporoblasts were enlarged. The polar capsules were malformed and the

  13. Structural effects of nogalamycin, an antibiotic antitumour agent, on DNA

    SciTech Connect

    Banerjee, T.; Mukhopadhyay, R.

    2008-09-19

    The structural changes of DNA, induced by the antitumour antibiotic nogalamycin, have been studied by atomic force microscopy (AFM). The transformation in the tertiary structure of 4361 bp long plasmid pBR322 DNA, after incubation with nogalamycin at 37 deg. C, has been monitored at the single molecule level. The AFM topographs of free DNA and the DNA-nogalamycin complex, incubated for 6, 12, 24, 36 and 48 h, reveal a gradual change from the circular supercoiled form having strand crossovers to the more compact plectonemic superhelix. With increasing incubation time, the extent of plectonemic coiling increases, indicating increasing level of drug binding via intercalative mode. Supportive evidences are obtained from the CD and UV-vis spectroscopic studies. To our knowledge, this is the first report on an AFM imaging study of the effects of nogalamycin, an anthracyclin intercalator, on DNA.

  14. Effects of competition and cooperation interaction between agents on networks in the presence of a market capacity

    NASA Astrophysics Data System (ADS)

    Sonubi, A.; Arcagni, A.; Stefani, S.; Ausloos, M.

    2016-08-01

    A network effect is introduced taking into account competition, cooperation, and mixed-type interaction among agents along a generalized Verhulst-Lotka-Volterra model. It is also argued that the presence of a market capacity undoubtedly enforces a definite limit on the agent's size growth. The state stability of triadic agents, i.e., the most basic network plaquette, is investigated analytically for possible scenarios, through a fixed-point analysis. It is discovered that: (i) market demand is only satisfied for full competition when one agent monopolizes the market; (ii) growth of agent size is encouraged in full cooperation; (iii) collaboration among agents to compete against one single agent may result in the disappearance of this single agent out of the market; and (iv) cooperating with two rivals may become a growth strategy for an intelligent agent.

  15. Effects of competition and cooperation interaction between agents on networks in the presence of a market capacity.

    PubMed

    Sonubi, A; Arcagni, A; Stefani, S; Ausloos, M

    2016-08-01

    A network effect is introduced taking into account competition, cooperation, and mixed-type interaction among agents along a generalized Verhulst-Lotka-Volterra model. It is also argued that the presence of a market capacity undoubtedly enforces a definite limit on the agent's size growth. The state stability of triadic agents, i.e., the most basic network plaquette, is investigated analytically for possible scenarios, through a fixed-point analysis. It is discovered that: (i) market demand is only satisfied for full competition when one agent monopolizes the market; (ii) growth of agent size is encouraged in full cooperation; (iii) collaboration among agents to compete against one single agent may result in the disappearance of this single agent out of the market; and (iv) cooperating with two rivals may become a growth strategy for an intelligent agent.

  16. Biogenic silver nanoparticles: efficient and effective antifungal agents

    NASA Astrophysics Data System (ADS)

    Netala, Vasudeva Reddy; Kotakadi, Venkata Subbaiah; Domdi, Latha; Gaddam, Susmila Aparna; Bobbu, Pushpalatha; Venkata, Sucharitha K.; Ghosh, Sukhendu Bikash; Tartte, Vijaya

    2016-04-01

    Biogenic synthesis of silver nanoparticles (AgNPs) by exploiting various plant materials is an emerging field and considered green nanotechnology as it involves simple, cost effective and ecofriendly procedure. In the present study AgNPs were successfully synthesized using aqueous callus extract of Gymnema sylvestre. The aqueous callus extract treated with 1nM silver nitrate solution resulted in the formation of AgNPs and the surface plasmon resonance (SPR) of the formed AgNPs showed a peak at 437 nm in the UV Visible spectrum. The synthesized AgNPs were characterized using Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), and X-ray diffraction spectroscopy (XRD). FTIR spectra showed the peaks at 3333, 2928, 2361, 1600, 1357 and 1028 cm-1 which revealed the role of different functional groups possibly involved in the synthesis and stabilization of AgNPs. TEM micrograph clearly revealed the size of the AgNPs to be in the range of 3-30 nm with spherical shape and poly-dispersed nature; it is further confirmed by Particle size analysis that the stability of AgNPs is due its high negative Zeta potential (-36.1 mV). XRD pattern revealed the crystal nature of the AgNPs by showing the braggs peaks corresponding to (111), (200), (220) and (311) planes of face-centered cubic crystal phase of silver. Selected area electron diffraction pattern showed diffraction rings and confirmed the crystalline nature of synthesized AgNPs. The synthesized AgNPs exhibited effective antifungal activity against Candida albicans, Candida nonalbicans and Candida tropicalis.

  17. Agentic extraversion modulates the cardiovascular effects of the dopamine D2 agonist bromocriptine.

    PubMed

    Wacker, Jan; Stemmler, Gerhard

    2006-07-01

    A recent psychobiological theory postulates a dopaminergic basis for the agency facet of extraversion, leading to the prediction that this personality trait modulates the psychophysiological effects of dopaminergic drugs. A single dose of the dopamine D2 receptor agonist bromocriptine reduces blood pressure in healthy volunteers. However, it is currently unknown whether this hypotensive effect of bromocriptine is modulated by agentic extraversion. Therefore, we measured resting cardiovascular activation in groups of healthy male volunteers either high or low in agentic extraversion, either under bromocriptine (1.25 mg) or placebo. Focusing the analyses on activation components derived from 18 cardiovascular variables, we found that bromocriptine reduces alpha-adrenergic activation in the sample as a whole, whereas the effects on beta-adrenergic and cholinergic activation are modulated by agentic extraversion.

  18. Formulation of radiographically detectable gastrointestinal contrast agents for magnetic resonance imaging: effects of a barium sulfate additive on MR contrast agent effectiveness.

    PubMed

    Rubin, D L; Muller, H H; Young, S W

    1992-01-01

    Complete and homogeneous distribution of gastrointestinal (GI) contrast media are important factors for their effective use in computed tomography as well as in magnetic resonance (MR) imaging. A radiographic method (using fluoroscopy or spot films) could be effective for monitoring intestinal filling with GI contrast agents for MR imaging (GICMR), but it would require the addition of a radiopaque agent to most GICMR. This study was conducted to determine the minimum amount of barium additive necessary to be radiographically visible and to evaluate whether this additive influences the signal characteristics of the GICMR. A variety of barium sulfate preparations (3-12% wt/vol) were tested in dogs to determine the minimum quantity needed to make the administered agent visible during fluoroscopy and on abdominal radiographs. Solutions of 10 different potential GI contrast agents (Gd-DTPA, ferric ammonium citrate, Mn-DPDP, chromium-EDTA, gadolinium-oxalate, ferrite particles, water, mineral oil, lipid emulsion, and methylcellulose) were prepared without ("nondoped") and with ("doped") the barium sulfate additive. MR images of the solutions in tubes were obtained at 0.38 T using 10 different spin-echo pulse sequences. Region of interest (ROI) measurements of contrast agent signal intensity (SI) were made. In addition, for the paramagnetic contrast media, the longitudinal and transverse relaxivity (R1 and R2) were measured. A 6% wt/vol suspension of barium was the smallest concentration yielding adequate radiopacity in the GI tract. Except for gadolinium-oxalate, there was no statistically significant difference in SI for doped and non-doped solutions with most pulse sequences used. In addition, the doped and nondoped solutions yielded R1 and R2 values which were comparable. We conclude that barium sulfate 6% wt/vol added to MR contrast agents produces a suspension with sufficient radiodensity to be viewed radiographically, and it does not cause significant alteration in

  19. Cardiometabolic risk in psoriasis: differential effects of biologic agents

    PubMed Central

    Kaplan, Mariana J

    2008-01-01

    Psoriasis is associated to an increased risk of cardiovascular (CV) complications. Overall, the pathogenic mechanisms involved in premature CV complications in psoriasis appear to be complex and multifactorial, with traditional and nontraditional risk factors possibly contributing to the increased risk. Based on what is known about the pathogenesis of psoriasis and extrapolating the current knowledge on CV complications in other inflammatory diseases, studies are needed to investigate if appropriate control of the inflammatory, immunologic and metabolic disturbances present in psoriasis can prevent the development of this potentially lethal complication. It is clear that there is a great need for heightened awareness of the increased risk for vascular damage in patients with psoriasis. It is also crucial to closely monitor patients with psoriasis for CV risk factors including obesity, hypertension, diabetes, and hyperlipidemia. Whether treatment regimens that effectively manage systemic inflammation will lead to prevention of CV complications in psoriasis needs to be investigated. Clearly, studies should focus on establishing the exact mechanisms that determine CV risk in psoriasis so that appropriate preventive strategies and treatment guidelines can be established. PMID:19337536

  20. The study of combined action of agents using differential geometry of dose-effect surfaces.

    PubMed

    Lam, G K

    1992-09-01

    Although graphic surfaces have been used routinely in the study of combined action of agents, they are mainly used for display purposes. In this paper, it is shown that useful mechanistic information can be obtained from an analytical study of these surfaces using the tools of differential geometry. From the analysis of some simple dose-effect surfaces, it is proposed that the intrinsic curvature, referred to in differential geometry as the Gaussian curvature, of a dose-effect surface can be used as a general criterion for the classification of interaction between different agents. This is analogous to the interpretation of the line curvature of a dose-effect curve as an indication of self-interaction between doses for an agent. In this framework, the dose-effect surface would have basic uniform fabric with zero curvature in the absence of interaction, tentatively referred to as null-interaction. Pictorially speaking, this fabric is distorted locally or globally like the stretching and shrinking of a rubber sheet by the presence of interaction mechanisms between different agents. Since self-interaction with dilution dummies does not generate intrinsic curvature, this criterion of null-interaction would describe the interaction between two truly different agents. It is shown that many of the published interaction mechanisms give rise to dose-effect surfaces with characteristic curvatures. This possible correlation between the intrinsic geometric curvature of dose-effect surfaces and the biophysical mechanism of interaction presents an interesting philosophical viewpoint for the study of combined action of agents.

  1. The Effects of Hemostatic Agents and Hypothermia Control in a Porcine Model

    DTIC Science & Technology

    2015-07-30

    investigated the effectiveness of hemostatic agents, specifically QCG in a hemodiluted or volume resuscitated state . In two separate studies, Johnson and...colleagues found that QCG was effective in a resuscitated and hemodiluted state , but they did not initially examine the additional effects of...suggest that QCG is effective in a hemodiluted state including prior dilution.11,26,27 Principal Investigator: Johnson, Arthur Don, PhD USU Project

  2. The mass media alone are not effective change agents.

    PubMed

    Ruijter, J M

    1991-01-01

    Social mobilization programs for immunization have been used by African leaders, however, coverage from 20% to 70% in capitals like Mogadishu, Maputo, and Dakar were the result of short campaigns rather than the consequence of knowledge, attitudes, and practices (KAP) improvement. One-party states relied on their network of cadres issuing decrees from the top down to enforce completion of these immunization campaigns. Sometimes resistance developed against these programs, as the military mobilized people (e.g., Somalia). These efforts became rather superficial once the temporary pressure evaporated. In Mogadishu coverage increased from 22% to 70% in 1985, and within a year it dropped back to 8% above the original level. Nigeria, Senegal, and Togo where they used regular mini campaigns had better results. Research data from Botswana, Kenya, Lesotho, Malawi, Mozambique, and Zambia were analyzed. In 1983 in Kenya 73% of health workers never advised their clients, and 82% were incompetent to do so. Data also showed that clinics provided the bulk of information to women aged 15-45 in lower income groups, but they rarely consulted village health workers. Radio and TV programs were not reaching people because radio ownership was not universal (47% in Zambia and 30% in Zimbabwe), and batteries were often not available. In addition, most people turned to the radio for entertainment. In 1989, vaccination coverage was 19% in Luanda, Angola, but only 5% of 232 respondents to an evaluation could name the immunizable diseases. An identical percentage was familiar with these diseases in a Zambian study in 1986. Media experts proposed dramas to raise interest, but innovative mass media programs of dissemination of the message advocated in the 1960s did not prove effective to bring about KAP changes. Training of health and paramedical personnel by mass organizations as initiated in Ethiopia may prove to be worthwhile.

  3. Effects of a bleaching agent with calcium on bovine enamel

    PubMed Central

    Alexandrino, Larissa; Gomes, Yasmin; Alves, Eliane; Costi, Hilton; Rogez, Hervé; Silva, Cecy

    2014-01-01

    Objective: This in vitro study analyzed the effects of a bleaching treatment containing 35% hydrogen peroxide (HP) with or without calcium on bovine enamel, using the Knoop hardness number (KHN), tristimulus colorimetry (TC), and scanning electron microscopy. Materials and Methods: Forty-five specimens were randomly divided into groups (n = 5), which included artificial saliva (negative control [NC]), 35% HP (positive control [PC]), and 35% HP Blue Calcium (HP Blue). The specimens were subjected to three bleaching sessions. During the sessions, the specimens were immersed in artificial saliva at 37°C. Before and after bleaching, KHN tests were conducted using a force of 25 gf for 5 s. TC was performed using the CIE-L*a*b* system and readouts were obtained at the following 4 time points: Before the bleaching treatment; after the first session, the second session, and the third session. The specimens were dehydrated and coated with gold, and the photomicrographs were analyzed in a double-blind manner with a LEO microscope. Results: Using one-way analysis of variance and Tukey's test (P < 0.05), a statistically significant difference was identified between the initial and final mean KHNs of the NC and PC groups, while the initial and final mean KHNs were not significantly different in the HP Blue group. The final mean values of ΔE, ΔL, and Δb of the PC and HP Blue groups were significantly higher than the initial values (P < 0.01 for both). The photomicrographs revealed no differences among the groups. Conclusions: Therefore, treatment with HP Blue prevented changes in the KHN without reducing the efficacy of bleaching. PMID:25202210

  4. Rabies virus infection of IMR-32 human neuroblastoma cells and effect of neurochemical and other agents.

    PubMed

    Lentz, T L; Fu, Y; Lewis, P

    1997-06-01

    IMR-32 human neuroblastoma cells are a continuous nerve cell line expressing neuronal nicotinic acetylcholine receptors. These cells were found to be susceptible to infection by rabies virus (CVS strain). After infection, viral antigen accumulated in the cell body in puncta and larger masses and spread out into the processes until at 3-4 days the entire cell was filled with antigen and lysed. A variety of chemical agents including cholinergic agonists and antagonists were tested for ability to inhibit infection of IMR-32 cells in a fluorescent focus assay. Agents found to inhibit infection were antibodies against the viral glycoprotein, gangliosides, a synthetic peptide of the neurotoxin-binding site of Torpedo acetylcholine receptor alpha1 subunit, alpha-bungarotoxin, and lysosomotropic agents. All other agents tested including other cholinergic ligands and synthetic peptides were not effective. Except for lysosomotropic agents, the agents which inhibited infection also inhibited attachment of virus to the cell surface. These results indicate that IMR-32 cells are a useful model in studying the interaction of a neurotropic virus with human neurons. The ability of alpha-bungarotoxin to inhibit infection suggests that neuronal alpha-bungarotoxin-binding receptors might serve as central nervous system receptors for rabies virus.

  5. An Agent-Based Modeling Approach for Determining Corn Stover Removal Rate and Transboundary Effects

    NASA Astrophysics Data System (ADS)

    Gan, Jianbang; Langeveld, J. W. A.; Smith, C. T.

    2014-02-01

    Bioenergy production involves different agents with potentially different objectives, and an agent's decision often has transboundary impacts on other agents along the bioenergy value chain. Understanding and estimating the transboundary impacts is essential to portraying the interactions among the different agents and in the search for the optimal configuration of the bioenergy value chain. We develop an agent-based model to mimic the decision making by feedstock producers and feedstock-to-biofuel conversion plant operators and propose multipliers (i.e., ratios of economic values accruing to different segments and associated agents in the value chain) for assessing the transboundary impacts. Our approach is generic and thus applicable to a variety of bioenergy production systems at different sites and geographic scales. We apply it to the case of producing ethanol using corn stover in Iowa, USA. The results from the case study indicate that stover removal rate is site specific and varies considerably with soil type, as well as other factors, such as stover price and harvesting cost. In addition, ethanol production using corn stover in the study region would have strong positive ripple effects, with the values of multipliers varying with greenhouse gas price and national energy security premium. The relatively high multiplier values suggest that a large portion of the value associated with corn stover ethanol production would accrue to the downstream end of the value chain instead of stover producers.

  6. An agent-based modeling approach for determining corn stover removal rate and transboundary effects.

    PubMed

    Gan, Jianbang; Langeveld, J W A; Smith, C T

    2014-02-01

    Bioenergy production involves different agents with potentially different objectives, and an agent's decision often has transboundary impacts on other agents along the bioenergy value chain. Understanding and estimating the transboundary impacts is essential to portraying the interactions among the different agents and in the search for the optimal configuration of the bioenergy value chain. We develop an agent-based model to mimic the decision making by feedstock producers and feedstock-to-biofuel conversion plant operators and propose multipliers (i.e., ratios of economic values accruing to different segments and associated agents in the value chain) for assessing the transboundary impacts. Our approach is generic and thus applicable to a variety of bioenergy production systems at different sites and geographic scales. We apply it to the case of producing ethanol using corn stover in Iowa, USA. The results from the case study indicate that stover removal rate is site specific and varies considerably with soil type, as well as other factors, such as stover price and harvesting cost. In addition, ethanol production using corn stover in the study region would have strong positive ripple effects, with the values of multipliers varying with greenhouse gas price and national energy security premium. The relatively high multiplier values suggest that a large portion of the value associated with corn stover ethanol production would accrue to the downstream end of the value chain instead of stover producers.

  7. The effects of a complexing agent on the transverse stability of cubic autocatalytic reaction fronts

    NASA Astrophysics Data System (ADS)

    Merkin, J. H.

    2009-07-01

    The effects of adding a complexing agent on the propagation and transverse stability of reaction fronts in a system based on cubic autocatalysis is considered. Adding the complexing agent is seen to reduce the propagation speed, alter the reaction dynamics and the concentration of the final reaction product of the propagating reaction fronts. A linear stability analysis (LSA) is considered to determine how the complexing agent affects the stability of planar reaction fronts through the numerical calculation of dispersion curves, plots of the growth rate σ against wavenumber k. These dispersion curves show that adding the complexing agent can make the system unstable when it would otherwise be stable and, when the system is diffusionally unstable without the complexing agent, weaken this instability. An analysis valid for small values of k is undertaken, which confirms the results from the LSA and indicates how the critical value Dc of the diffusion coefficient ratio D for the onset of an instability is changed by the addition of the complexing agent.

  8. Effect of bulking agents on maturity and gaseous emissions during kitchen waste composting.

    PubMed

    Yang, Fan; Li, Guo Xue; Yang, Qing Yuan; Luo, Wen Hai

    2013-10-01

    This study investigated the effect of bulking agents on the maturity and gaseous emissions of composting kitchen waste. Three different bulking agents (cornstalks, sawdust, and spent mushroom substrate) were used to compost kitchen waste under aerobic conditions in 60-L reactors for a 28-d period. A control treatment was also studied using kitchen waste without a bulking agent. During the experiment, maturity indexes such as temperature, pH value, C/N ratio, and germination index were determined, and continuous measurements of leachate and gaseous emissions (CH₄, N₂O, and NH₃) were taken. The results showed that all of the composts with bulking agents reached the required maturity standard, and the addition of spent mushroom substrate gave the highest maturity (C/N ratio decreased from 23 to 16 and germination index increased from 53% to 111%). The bulking agents also reduced leachate production and CH₄ and N₂O emissions, but had little impact on NH3 emissions. Composting with sawdust as a bulking agent was found to emit less total greenhouse gas (33 kg CO₂-eqt(-1) dry matter) than the other treatments.

  9. Effect of curing agent and temperature on the rheological behavior of epoxy resin systems.

    PubMed

    Zhao, Chenhui; Zhang, Guangcheng; Zhao, Lei

    2012-07-17

    The effect of curing agent (6610) content and temperature on the rheological behavior of the epoxy resin CYD-128 was studied by DSC analysis and viscosity experiments. The results show that the resin system meets the requirements of processing technology. A complete reaction occurs when the curing agent content (40 parts per hundred resin, phr) is a little higher than the theoretical value (33.33 phr), while the degree of reaction of the resin system is reduced when the curing agent content is lower (25.00 phr) than theoretical value. However, excessive curing agent (50.00 phr) results in a lower reaction rate. Curing agent content has little influence on gel time when curing agent content exceeded 33.33 phr and the temperature was less than 70 °C. The isothermal viscosity-time curves shift towards the -x axis when the temperature rises from 50 °C to 80 °C. Meanwhile, higher temperature results in higher reaction rates.

  10. Synergistic Effects of Nonthermal Plasma and Disinfecting Agents against Dental Biofilms In Vitro

    PubMed Central

    Koban, Ina; Geisel, Marie Henrike; Holtfreter, Birte; Jablonowski, Lukasz; Hübner, Nils-Olaf; Matthes, Rutger; Masur, Kai; Weltmann, Klaus-Dieter; Kramer, Axel; Kocher, Thomas

    2013-01-01

    Aim. Dental biofilms play a major role in the pathogenesis of many dental diseases. In this study, we evaluated the synergistic effect of atmospheric pressure plasma and different agents in dentistry on the reduction of biofilms. Methods and Results. We used monospecies (S. mutans) and multispecies dental biofilm models grown on titanium discs in vitro. After treatment with one of the agents, the biofilms were treated with plasma. Efficacy of treatment was determined by the number of colony forming units (CFU) and by live-dead staining. For S. mutans biofilms no colonies could be detected after treatment with NaOCl or H2O2. For multispecies biofilms the combination with plasma achieved a higher CFU reduction than each agent alone. We found an additive antimicrobial effect between argon plasma and agents irrespective of the treatment order with cultivation technique. For EDTA and octenidine, antimicrobial efficacy assessed by live-dead staining differed significantly between the two treatment orders (P < 0.05). Conclusions. The effective treatment of dental biofilms on titanium discs with atmospheric pressure plasma could be increased by adding agents in vitro. PMID:24159388

  11. Level Up, My-Pet: The Effects of Level-up Mechanism of Educational Agents on Student Learning

    ERIC Educational Resources Information Center

    Chen, Zhi-Hong; Chao, Po-Yao; Hsu, Ming-Chieh; Teng, Chin-Hung

    2013-01-01

    A number of studies have been devoted to investigating the influence of educational agents on different aspects of student learning. However, little attention has been paid to the effects of the level-up mechanism of educational agents on students although this is a significant issue. Thus, this study develops an educational agent with the…

  12. Enhancement of pharmacological effects of uricosuric agents by concomitant treatment with pyrazinamide in rats.

    PubMed

    Taniguchi, Tetsuya; Ashizawa, Naoki; Matsumoto, Koji; Iwanaga, Takashi

    2017-03-01

    Our goal was to establish a model for the evaluation of the effects of uricosuric agents and to clarify the underlying mechanism(s). The effects of a uricosuric agent co-treated with pyrazinamide, an anti-tubercular agent, on urate handling were examined in rats. Furthermore, the effects of uricosuric agents on urate uptake were evaluated using the vesicles of rat renal brush-border membrane. Treatment with probenecid, at a dose of 100 mg/kg, significantly increased the urinary urate to creatinine ratio (UUA/UCRE) in pyrazinamide-treated rats although the same treatment did not produce any uricosuric effects in intact rats. In this model, the urinary excretion of pyrazinecarboxylic acid (PZA), an active metabolite of pyrazinamide, was decreased by probenecid and indicated an inverse correlation between urinary excretion of urate and PZA. Furthermore, in the examination using FYU-981, a potent uricosuric agent, a more than 10-fold leftward shift of the dose-response relationship of the uricosuric effect was observed in pyrazinamide-treated rats when compared with intact rats. In the in vitro study, the treatment of the vesicles of rat renal brush-border membrane with PZA produced an increased urate uptake, which was inhibited by uricosuric agents. The pyrazinamide-treated model used in the present study seems to be valuable for the evaluation of uricosurics because of its higher sensitivity to these drugs when compared to intact rats, and this is probably due to the enhanced urate reabsorption accompanied with trans-stimulated PZA transport at the renal brush-border membrane.

  13. Investigation of the effect of scattering agent and scattering albedo on modulated light propagation in water.

    PubMed

    Mullen, Linda; Alley, Derek; Cochenour, Brandon

    2011-04-01

    A recent paper described experiments completed to study the effect of scattering on the propagation of modulated light in laboratory tank water [Appl. Opt.48, 2607 (2009)APOPAI0003-693510.1364/AO.48.002607]. Those measurements were limited to a specific scattering agent (Maalox antacid) with a fixed scattering albedo (0.95). The purpose of this paper is to study the effects of different scattering agents and scattering albedos on modulated light propagation in water. The results show that the scattering albedo affects the number of attenuation lengths that the modulated optical signal propagates without distortion, while the type of scattering agent affects the degree to which the modulation is distorted with increasing attenuation length.

  14. Identification of small molecule Hes1 modulators as potential anticancer chemotherapeutics.

    PubMed

    Sail, Vibhavari; Hadden, M Kyle

    2013-03-01

    Hes1 is a key transcriptional regulator primarily controlled by the Notch signaling pathway, and recent studies have demonstrated both an oncogenic and tumor suppressor role for Hes1, depending on the cell type. Small molecules that activate and inhibit Hes1 activity hold promise as future anticancer chemotherapeutics. We have utilized a cell-based dual luciferase assay to identify modulators of Hes1 expression in a medium-throughput format. A modest screen was performed in HCT-116 colon cancer cell lines, and two small molecules were identified and characterized as Hes1 regulators. Compound 3 induced Hes1 expression and exhibited anticancer effects in pulmonary carcinoid tumor cells, a cell type in which the upregulated Notch/Hes1 signaling plays a tumor suppressive role. Treatment of HCT-116 cells with compound 12 resulted in Hes1 downregulation and antitumor effects.

  15. [Effects of ground cover and water-retaining agent on winter wheat growth and precipitation utilization].

    PubMed

    Wu, Ji-Cheng; Guan, Xiu-Juan; Yang, Yong-Hui

    2011-01-01

    An investigation was made at a hilly upland in western Henan Province to understand the effects of water-retaining agent (0, 45, and 60 kg x hm(-2)), straw mulching (3000 and 6000 kg x hm(-2)), and plastic mulching (thickness < 0.005 mm) on winter wheat growth, soil moisture and nutrition conditions, and precipitation use. All the three measures promoted winter wheat growth, enhanced grain yield and precipitation use efficiency, and improved soil moisture and nutritional regimes. These positive effects were more obvious when the straw- or plastic mulching was combined with the use of water-retaining agent. Comparing with the control, all the measures increased the soil moisture content at different growth stages by 0.1%-6.5%. Plastic film mulching had the best water-retention effect before jointing stage, whereas water-retaining agent showed its best effect after jointing stage. Soil moisture content was the lowest at flowering and grain-filling stages. Land cover increased the grain yield by 2.6%-20.1%. The yield increment was the greatest (14.2%-20.1%) by the combined use of straw mulching and water-retaining agent, followed by plastic mulching combined with water-retaining agent (11.9% on average). Land cover also improved the precipitation use efficiency (0.4-3.2 kg x mm(-1) x hm(-2)) in a similar trend as the grain yield. This study showed that land cover and water-retaining agent improved soil moisture and nutrition conditions and precipitation utilization, which in turn, promoted the tillering of winter wheat, and increased the grain number per ear and the 1000-grain mass.

  16. Evaluation of Chemotherapeutic Agents Against Malaria, Drugs, Diet, and Biological Response Modifiers.

    DTIC Science & Technology

    1991-10-29

    In experiment 76 the antioxidant Coenzyme Q10 (ubiquinone 50) was tested to see if it would replace vitamin E as an antioxidant and influence the...low whether started at 3 weeks of age or 4 weeks of age. 49 In experiment 76 the antioxidant coenzyme Q10 (ubiquinone 50) administered PO at 100, 36 or...line has remained stable under drug pressure for this year. Co-enzyme Q10 did not act as an antioxidant like vitamin E during a malarial infection

  17. Selenium is a Chemotherapeutic Agent for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2006-02-01

    receptor activity by a hammerhead ribozyme . Mol Endrocrinol 1998;12:1558-1566. 10. Ko YJ, Devi GR, London CA, et al. Androgen receptor down-regulation...Strategic targeting of the AR with ribozymes , antisense oligomers, and small interfering RNAs has been shown to significantly inhibit prostate cancer

  18. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2005-05-01

    16) gives 00 00 ft.[HbO2]0 .(-K)-e-"t .dt 1 J(i().Ie-’ .d(xt) 0" 0=_. (17) f[HbO 2 10. (-K).e-l .dt fe -lt .d(ta) 0 0 Equation (17) indicates that the...Zhao, D., Constantinescu, A., and Mason, R. P., (2004), "Comparison of BOLD contrast and Gd -DTPA dynamic contrast enhanced imaging in rat prostate tumor...I. Chau, and Z. Grossman, "Functional magnetic resonance ( fMR ) imaging of a rat brain tumor model: implications for evaluation of tumor

  19. 1-Alpha Hydroxyvitamin D(5) as a Chemotherapeutic and Possibly Chemopreventive Agent

    DTIC Science & Technology

    2007-03-01

    any underlying conditions that would contraindicate therapy with study treatment (or allergies to D5 used in this study). 6.2.5 Patients with prior...D2. Arch Biochem Biophys. 197:119-25. [10] Norman AW. (1998) Sunlight, season , skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral...cases of breast, colon, and prostate cancer diagnosed in the summer and fall—the seasons when serum levels of vitamin Dj are expected to be the highest

  20. 1 ALPHA-Hydroxyvitamin D5 as a Chemotherapeutic and Possibly Chemopreventive Agent

    DTIC Science & Technology

    2004-09-01

    size 0; Apothecary Products, Inc.) 4. Preparation of 10 jig dosage: a. Weigh 3 gm of cornstarch, NF b. Using a syringe, measure 0.5 mL D5 solution...cornstarch d. Weigh 150 mg of D5/cornstarch mixture to fill each of 52 capsules (size 0; Apothecary Products, Inc.) 5. Preparation of 15 jig dosage: a...capsules (size 0; Apothecary Products, Inc.) lchydroxyvitamin D5 Phase 1/11 Trial Protocol (Version #10 (06/30/04) - Page 32 of 33 6. Preparation of 20

  1. Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

    PubMed Central

    Chatelut, E; White-Koning, M L; Mathijssen, R HJ; Puisset, F; Baker, S D; Sparreboom, A

    2012-01-01

    Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patient's dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria. Methods: Three BSA bands were defined: BSA<1.7 m2, 1.7 m2⩽BSA<1.9 m2, BSA⩾1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug. Results: For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between −14% and +22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P<0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs. Conclusion: For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure. PMID:22929884

  2. Selenium is a Chemotherapeutic Agent for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2007-12-01

    to the AR without decreasing AR levels. Strategic targeting of the AR with ribozymes , antisense oligomers, and small interfering RNAs has been shown... ribozyme . Mol Endrocrinol 1998;12:1558-1566. 20 10. Ko YJ, Devi GR, London CA, et al. Androgen receptor down-regulation in prostate cancer with

  3. Monitoring of Breast Tumor Response to Local Chemotherapeutic Agent Delivered by Biodegradable Fibers

    DTIC Science & Technology

    2006-05-01

    Sausalito: University science books) 73-77 (1997) 46. H. Liu, A. H. Hielscher , F. K. Tittel, S. L. Jacques, and B. Chance, “Influence of blood...Reson. Imaging, 15, 41-57 (2004). 92. A. Y. Bluestone, M. Stewart, J. Lasker, G.S. Absoulaev, and A. H. Hielscher , “Three-dimensional optical...during forearm ischemia J. Appl. Physiol. 64 2449–57 [44] Liu H, Hielscher A H, Tittel F K, Jacques S L and Chance B 1995 Influence of blood vessels on

  4. Measuring the effects of topically applied skin optical clearing agents and modeling the effects and consequences for laser therapies

    NASA Astrophysics Data System (ADS)

    Verkruysse, Wim; Khan, Misbah; Choi, Bernard; Svaasand, Lars O.; Nelson, J. Stuart

    2005-04-01

    Human skin prepared with an optical clearing agent manifests reduced scattering as a result of de-hydration and refractive index matching. This has potentially large effects for laser therapies of several skin lesions such as port wine stain, hair removal and tattoo removal. With most topically applied clearing agents the clearing effect is limited because they penetrate poorly through the intact superficial skin layer (stratum corneum). Agent application modi other than topical are impractical and have limited the success of optical clearing in laser dermatology. In recent reports, however, a mixture of lipofylic and hydrofylic agents was shown to successfully penetrate through the intact stratum corneum layer which has raised new interest in this field. Immediately after application, the optical clearing effect is superficial and, as the agent diffuses through the skin, reduced scattering is manifested in deeper skin layers. For practical purposes as well as to maximize therapeutic success, it is important to quantify the reduced scattering as well as the trans-cutaneous transport dynamics of the agent. We determined the time and tissue depth resolved effects of optically cleared skin by inserting a microscopic reflector array in the skin. Depth dependent light intensity was measured by quantifying the signal of the reflector array with optical coherence tomography. A 1-dimensional mass diffusion model was used to estimate a trans-cutaneous transport diffusion constant for the clearing agent mixture. The results are used in Monte Carlo modeling to determine the optimal time of laser treatment after topical application of the optical clearing agent.

  5. Lithium Modulates Autophagy in Esophageal and Colorectal Cancer Cells and Enhances the Efficacy of Therapeutic Agents In Vitro and In Vivo

    PubMed Central

    O’Donovan, Tracey R.; Rajendran, Simon; O’Reilly, Seamus; McKenna, Sharon L.

    2015-01-01

    Many epithelial cancers, particularly gastrointestinal tract cancers, remain poor prognosis diseases, due to resistance to cytotoxic therapy and local or metastatic recurrence. We have previously shown that apoptosis incompetent esophageal cancer cells induce autophagy in response to chemotherapeutic agents and this can facilitate their recovery. However, known pharmacological inhibitors of autophagy could not enhance cytotoxicity. In this study, we have examined two well known, clinically approved autophagy inducers, rapamycin and lithium, for their effects on chemosensitivity in apoptosis incompetent cancer cells. Both lithium and rapamycin were shown to induce autophagosomes in esophageal and colorectal cancer cells by western blot analysis of LC3 isoforms, morphology and FACS quantitation of Cyto-ID or mCherry-GFP-LC3. Analysis of autophagic flux indicates inefficient autophagosome processing in lithium treated cells, whereas rapamycin treated cells showed efficient flux. Viability and recovery was assessed by clonogenic assays. When combined with the chemotherapeutic agent 5-fluorouracil, rapamycin was protective. In contrast, lithium showed strong enhancement of non-apoptotic cell death. The combination of lithium with 5-fluorouracil or oxaliplatin was then tested in the syngenic mouse (balb/c) colorectal cancer model—CT26. When either chemotherapeutic agent was combined with lithium a significant reduction in tumor volume was achieved. In addition, survival was dramatically increased in the combination group (p < 0.0001), with > 50% of animals achieving long term cure without re-occurrence (> 1 year tumor free). Thus, combination treatment with lithium can substantially improve the efficacy of chemotherapeutic agents in apoptosis deficient cancer cells. Induction of compromised autophagy may contribute to this cytotoxicity. PMID:26248051

  6. Effect of oxatomide, an antiallergic agent, on QT interval in dogs.

    PubMed

    Iwamoto, K; Ikeda, J; Nito, M; Kosaka, N; Ichikawa, S; Ohmori, K; Sakai, K

    2001-01-01

    Oxatomide (CAS 60607-34-3, KW-4354) is an effective antiallergic agent for allergic rhinitis, urticaria, pruritus cutaneous, and eczema/dermatitis, etc. Terfenadine (CAS 50679-08-8) and astemizole (CAS 68844-77-9), antiallergic agents, have been reported to induce QT prolongation leading to serious ventricular arrhythmia (torsades de pointes) as cardiovascular adverse effects. The present study was carried out to determine whether oxatomide and terfenadine have effects on QT interval as a single drug or in combination with itraconazole (CAS 84625-61-6), an antifungal agent with a CYP3A4 inhibitory effect, in conscious dogs. Terfenadine alone induced QT prolongation at the dose of 30 mg/kg p.o. When itraconazole was administered at the dose of 100 mg/kg p.o. 1 h before terfenadine administration, terfenadine induced QT prolongation at the dose of 10 mg/kg p.o. On the other hand, oxatomide did not induce QT prolongation either as a single agent at the dose of 30 mg/kg p.o. or in combination with itraconazole at the dose of 10 mg/kg p.o. The results present no evidence that oxatomide has the potential to provoke ventricular arrhythmia.

  7. Supporting Multimedia Learning with Visual Signalling and Animated Pedagogical Agent: Moderating Effects of Prior Knowledge

    ERIC Educational Resources Information Center

    Johnson, A. M.; Ozogul, G.; Reisslein, M.

    2015-01-01

    An experiment examined the effects of visual signalling to relevant information in multiple external representations and the visual presence of an animated pedagogical agent (APA). Students learned electric circuit analysis using a computer-based learning environment that included Cartesian graphs, equations and electric circuit diagrams. The…

  8. Indirect ecological effects in invaded landscapes: Spillover and spillback from biological control agents to native analogues

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Biological control remains an effective option for managing large-scale weed problems in natural areas. The predation or parasitism of biological control agents by other species present in the introduced range (biotic resistance) is well studied and is often cited as the cause for a lack of establis...

  9. NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

    EPA Science Inventory

    Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
    S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

    Dose-response estimation is a critical feature of risk assessment. It can be...

  10. Teachable Agents and the Protege Effect: Increasing the Effort towards Learning

    ERIC Educational Resources Information Center

    Chase, Catherine C.; Chin, Doris B.; Oppezzo, Marily A.; Schwartz, Daniel L.

    2009-01-01

    Betty's Brain is a computer-based learning environment that capitalizes on the social aspects of learning. In Betty's Brain, students instruct a character called a Teachable Agent (TA) which can reason based on how it is taught. Two studies demonstrate the "protege effect": students make greater effort to learn for their TAs than they do…

  11. Diffuse reflectance study of the effects of bleaching agents in damaged dental pieces

    NASA Astrophysics Data System (ADS)

    Bante-Guerra, J.; Trejo-Tzab, R.; Macias, J. D.; Quintana, P.; Alvarado-Gil, J. J.

    2011-03-01

    One of the most important subjects of interest in dentistry and teeth preservation is related to the effects of bleaching agents on the integrity of the dental pieces. This is especially crucial when teeth surface has received some damage, generated by chemical, biological and mechanical agents or weathering in the case of dental pieces recovered from burial sites. In this work the time evolution of the effects of bleaching agents on the surface of dental pieces is monitored using diffuse reflectance in the visible spectrum is reported. The effects were monitored in teeth previously subject to chemical agents. Bleaching was induced using commercial whitening products. It is shown that the time evolution of the reflectance depends strongly on the condition of the surface as well as on the thickness of enamel. Additionally the colorimetric analysis of the samples during the bleaching is presented. This is especially useful in for comparing with previous studies. In order to complement our studies, the effects of the bleaching on the surface of the teeth were monitored by scanning electron microscopy.

  12. Effect of pharmacologic agents on the function of the hypothermically preserved dog kidney during normothermic reperfusion.

    PubMed

    Ploeg, R J; Vreugdenhil, P; Goossens, D; McAnulty, J F; Southard, J H; Belzer, F O

    1988-06-01

    We examined how a combination of pharmacologic agents ("rescue" agents) affect the function of hypothermically preserved dog kidneys at the time of reperfusion. Dog kidneys were preserved either by simple cold storage in EuroCollins' solution for 24 or 48 hours or by continuous perfusion at 5 degrees C in Belzer's gluconate-hydroxyethyl starch solution for as long as 5 days. After preservation, renal functions were measured with the isolated perfused kidney model. Kidneys were reperfused at normothermia either with or without the addition of a combination of rescue agents to the reperfusion medium. The rescue agents studied were allopurinol (1 mmol/L); superoxide dismutase (32,000 U/L); catalase (137,500 U/L); dimethylthiourea (3 mmol/L); glutathione (3 mmol/L); desferrioxamine (0.2 gm/L), for protection against O2 free radical injury and lipid peroxidation injury; verapamil (25 mg/L), as a Ca channel blocker; and ATP-MgCl2 (0.3 mmol/L), to stimulate energy metabolism. The renal functions we measured were glomerular filtration rate (GFR) (creatinine clearance), urine production, perfusate flow, urinary protein concentration, Na reabsorptive capacity, and tissue concentrations of ATP, K, and total tissue water. GFR was reduced by 75% to 90% after all periods of preservation, and the rescue agents had no effect on GFR. Sodium reabsorption was reduced from 98% to a range of 40% to 50% after 48 hours of cold storage or 5 days of machine perfusion and was not increased by rescue agents. There was a time-dependent increase in the amount of urine protein that was not affected by rescue agents. The addition of rescue agents did not affect total tissue water or concentrations of ATP or K in kidneys after normothermic reperfusion. These results demonstrate that pharmacologic agents previously suggested to suppress reperfusion damage in kidneys are not effective in this model. Therefore it is likely that kidneys damage occurs primarily during preservation, which suggest that

  13. Effectiveness of dynamic rescheduling in agent-based flexible manufacturing systems

    NASA Astrophysics Data System (ADS)

    Saad, Ashraf; Biswas, Gautam; Kawamura, Kazuhiko; Johnson, Eric M.

    1997-12-01

    This work has been developed within the framework of agent- based decentralized scheduling for flexible manufacturing systems. In this framework, all workcells comprising the manufacturing system, and the products to be generated, are modeled via intelligent software agents. These agents interact dynamically using a bidding production reservation (BPRS) scheme, based on the Contract Net Protocol, to devise the production schedule for each product unit. Simulation studies of a job shop have demonstrated the gains in performance achieved by this approach over heuristic dispatching rules commonly used in industry. Manufacturing environments are also prone to operational uncertainties such as variations in processing times and machine breakdowns. In order to cope with these uncertainties, the BPRS algorithm has been extended for dynamic rescheduling to also occur in a fully decentralized manner. The resulting multi-agent rescheduling scheme results in decentralized control of flexible manufacturing systems that are capable of responding dynamically to such operational uncertainties, thereby enhancing the robustness and fault tolerance of the proposed scheduling approach. This paper also presents the effects of the proposed agent-based decentralized scheduling approach on the performance of the underlying flexible manufacturing system under a variety of production and scheduling scenarios, including forward and backward scheduling. Future directions for this work include applying the proposed scheduling approach to other advanced manufacturing areas such as agile and holonic manufacturing.

  14. Effect of using miscible and immiscible healing agent on solid state self-healing system

    NASA Astrophysics Data System (ADS)

    Makenan, Siti Mastura; Jamil, Mohd Suzeren Md.

    2014-09-01

    The aim of this study is to identify the effect of using various healing agent which are miscible; poly(bisphenol-A-co-epichlorohydrin), and immiscible; poly(ethylene-co-acetate) and poly(ethylene-co-acrylic acid), on self-healing resin system. The specimens were analysed by Fourier-transform Infrared Spectrometer (FTIR), Dynamic Mechanical Thermal Analysis (DMTA), and izod test. Optical image of the sample morphology was observed using optical microscope. Healing efficiencies (HE) were evaluated using izod test. The concept of healing recovery was proved based on the use of miscible and immiscible healing agent. From the results, it can be concluded that the healable resin with miscible healing agent has the highest HE within the third healing cycle.

  15. Is matching ruthenium with dithiocarbamato ligands a potent chemotherapeutic weapon in oncology?

    PubMed

    Nardon, Chiara; Brustolin, Leonardo; Fregona, Dolores

    2016-01-01

    In the last years, several metal-based compounds have been designed and biologically investigated worldwide in order to obtain chemotherapeutics with a better toxicological profile and comparable or higher antiblastic activity than the clinically-established platinum-based drugs. In this context, researchers have addressed their attention to alternative nonplatinum derivatives able to maximize the anticancer activity of the new drugs and to minimize the side effects. Among them, a number of ruthenium complexes have been developed, including the compounds NAMI-A and KP1019, now in clinical trials. Here, we report the results collected so far for a particular class of ruthenium complexes - the ruthenium(II/III)-dithiocarbamates - which proved more potent than cisplatin in vitro, even at nanomolar concentrations, against a wide panel of human tumor cell lines.

  16. Effects of Several Flame Retardants and Curing Agents on the Fire and Mechanical Properties of Epoxy Resin

    NASA Astrophysics Data System (ADS)

    Li, Pei; Min, Yang; Ban, Da-Ming

    2016-05-01

    Effect of different flame retardant (FR) and curing agent on the epoxy resin was investigated by limiting oxygen index (LOI), mechanical properties and FTIR. The results show that flame retardant effect of PODOPP is better than PSDPP. The curing agent order is: m-phenylenediamine>ethanediamine> polyethylene polyamine. The effect of flame retardant behaviors better when synergist OMMT was added.

  17. Circulatory therapeutics: use of antihypertensive agents and their effects on the vasculature

    PubMed Central

    Schiffrin, Ernesto L

    2010-01-01

    Abstract This review addresses the use of the different antihypertensive agents currently available and some in development, and their effects on the vasculature. The different classes of agents used in the treatment of hypertension, and the results of recent large clinical trials, dosing protocols and adverse effects are first briefly summarized. The consequences on blood vessels of the use of antihypertensive drugs and the differential effects on the biology of large and small arteries resulting in modulation of vascular remodelling and dysfunction in hypertensive patients are then described. Large elastic conduit arteries exhibit outward hypertrophic remodelling and increased stiffness, which contributes to raise systolic blood pressure and afterload on the heart. Small resistance arteries undergo eutrophic or hypertrophic inward remodelling, and impair tissue perfusion. By these mechanisms both large and small arteries may contribute to trigger cardiovascular events. Some antihypertensive agents correct these changes, which could contribute to improved outcome. The mechanisms that at the level of the vascular wall lead to remodelling and can be beneficially affected by antihypertensive agents will also be addressed. These include vasoconstriction, growth and inflammation. The molecular pathways contributing to growth and inflammation will be summarily described. Further identification of these signalling pathways should allow identification of novel targets leading to development of new and improved medications for the treatment of hypertension and cardiovascular disease. PMID:20345850

  18. Growth inhibitory effect of shelf life extending agents on Bacillus subtilis IAM 1026.

    PubMed

    Mitsuboshi, Saori; Obitsu, Rie; Muramatsu, Kanako; Furube, Kentaro; Yoshitake, Shigehiro; Kiuchi, Kan

    2007-06-01

    Natural shelf life extending agents and sugar fatty acid esters that might inhibit the growth of B. subtilis IAM 1026 were screened, and the effective agents were as follows: beta-thujaplicin (Hinokitiol) and chitosan, inhibited the growth of IAM 1026 at a concentration of 0.001% ; epsilon-polylysine and M-1695 (a sugar fatty acid ester) at 0.005%; citrus seed extract, thiamin lauryl sulfate, and grapefruit seed extract at 0.01%; CT-1695 and L-1695 (sugar fatty acid esters) at 0.05%; pectin digests and SM-800 (a sugar fatty acid ester) at 0.5%; water pepper seed extract and the sugar fatty acid esters SM-1000 and CE-1695 at 1.0%. The growth inhibitory effects of the agents in custard cream were not necessarily similar to those in liquid culture. The agent that showed the highest inhibitory effect in custard cream was 0.3% beta-thujaplicin, followed by 0.3% epsilon-polylysine.

  19. Impact of release rates on the effectiveness of augmentative biological control agents.

    PubMed

    Crowder, David W

    2007-01-01

    To access the effect of augmentative biological control agents, 31 articles were reviewed that investigated the impact of release rates of 35 augmentative biological control agents on the control of 42 arthropod pests. In 64% of the cases, the release rate of the biological control agent did not significantly affect the density or mortality of the pest insect. Results where similar when parasitoids or predators were utilized as the natural enemy. Within any order of natural enemy, there were more cases where release rates did not affect augmentative biological control than cases where release rates were significant. There were more cases in which release rates did not affect augmentative biological control when pests were from the orders Hemiptera, Acari, or Diptera, but not with pests from the order Lepidoptera. In most cases, there was an optimal release rate that produced effective control of a pest species. This was especially true when predators were used as a biological control agent. Increasing the release rate above the optimal rate did not improve control of the pest and thus would be economically detrimental. Lower release rates were of ten optimal when biological control was used in conjunction with insecticides. In many cases, the timing and method of biological control applications were more significant factors impacting the effectiveness of biological control than the release rate. Additional factors that may limit the relative impact of release rates include natural enemy fecundity, establishment rates, prey availability, dispersal, and cannibalism.

  20. Impact of Release Rates on the Effectiveness of Augmentative Biological Control Agents

    PubMed Central

    Crowder, David W.

    2007-01-01

    To access the effect of augmentative biological control agents, 31 articles were reviewed that investigated the impact of release rates of 35 augmentative biological control agents on the control of 42 arthropod pests. In 64% of the cases, the release rate of the biological control agent did not significantly affect the density or mortality of the pest insect. Results where similar when parasitoidsor predators were utilized as the natural enemy. Within any order of natural enemy, there were more cases where release rates did not affect augmentative biological control than cases where release rates were significant. There were more cases in which release rates did not affect augmentative biological control when pests were from the orders Hemiptera, Acari, or Diptera, but not with pests from the order Lepidoptera. In most cases, there was an optimal release rate that produced effective control of a pest species. This was especially true when predators were used as a biological control agent. Increasing the release rate above the optimal rate did not improve control of the pest and thus would be economically detrimental. Lower release rates were of ten optimal when biological control was used in conjunction with insecticides. In many cases, the timing and method of biological control applications were more significant factors impacting the effectiveness of biological control than the release rate. Additional factors that may limit the relative impact of release rates include natural enemy fecundity, establishment rates, prey availability, dispersal, and cannibalism. PMID:20307240

  1. Loss of Cytoplasmic CDK1 Predicts Poor Survival in Human Lung Cancer and Confers Chemotherapeutic Resistance

    PubMed Central

    Zhang, Chunyu; Elkahloun, Abdel G.; Robertson, Matthew; Gills, Joell J.; Tsurutani, Junji; Shih, Joanna H.; Fukuoka, Junya; Hollander, M. Christine; Harris, Curtis C.; Travis, William D.; Jen, Jin; Dennis, Phillip A.

    2011-01-01

    The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. PMID:21887332

  2. Identification of a candidate single-nucleotide polymorphism related to chemotherapeutic response through a combination of knowledge-based algorithm and hypothesis-free genomic data.

    PubMed

    Takahashi, Hiro; Kaniwa, Nahoko; Saito, Yoshiro; Sai, Kimie; Hamaguchi, Tetsuya; Shirao, Kuniaki; Shimada, Yasuhiro; Matsumura, Yasuhiro; Ohtsu, Atsushi; Yoshino, Takayuki; Takahashi, Anna; Odaka, Yoko; Okuyama, Misuzu; Sawada, Jun-ichi; Sakamoto, Hiromi; Yoshida, Teruhiko

    2013-12-01

    Inter-individual variations in drug responses among patients are known to cause serious problems in medicine. Genome-wide association study (GWAS) is powerful for examining single-nucleotide polymorphisms (SNPs) and their relationships with drug response variations. However, no significant SNP has been identified using GWAS due to multiple testing problems. Therefore, we propose a combination method consisting of knowledge-based algorithm, two stages of screening, and permutation test for identifying SNPs in the present study. We applied this method to a genome-wide pharmacogenomics study for which 109,365 SNPs had been genotyped using Illumina Human-1 BeadChip for 119 gastric cancer patients treated with fluoropyrimidine. We identified rs2293347 in epidermal growth factor receptor (EGFR) is as a candidate SNP related to chemotherapeutic response. The p value for the rs2293347 was 2.19 × 10(-5) for Fisher's exact test, and the p value was 0.00360 for the permutation test (multiple testing problems are corrected). Additionally, rs2293347 was clearly superior to clinical parameters and showed a sensitivity value of 55.0% and specificity value of 94.4% in the evaluation by using multiple regression models. Recent studies have shown that combination chemotherapy of fluoropyrimidine and EGFR-targeting agents is effective for gastric cancer patients highly expressing EGFR. These results suggest that rs2293347 is a potential predictive factor for selecting chemotherapies, such as fluoropyrimidine alone or combination chemotherapies.

  3. Chemotherapeutic strategies for reducing transmission of Plasmodium vivax malaria.

    PubMed

    Douglas, Nicholas M; John, George K; von Seidlein, Lorenz; Anstey, Nicholas M; Price, Ric N

    2012-01-01

    Effective use of anti-malarial drugs is key to reducing the transmission potential of Plasmodium vivax. In patients presenting with symptomatic disease, treatment with potent and relatively slowly eliminated blood schizontocidal regimens administered concurrently with a supervised course of 7 mg/kg primaquine over 7-14 days has potential to exert the greatest transmission-blocking benefit. Given the spread of chloroquine-resistant P. vivax strains, the artemisinin combination therapies dihydroartemisinin + piperaquine and artesunate + mefloquine are currently the most assured means of preventing P. vivax recrudescence. Preliminary evidence suggests that, like chloroquine, these combinations potentiate the hypnozoitocidal effect of primaquine, but further supportive evidence is required. In view of the high rate of P. vivax relapse following falciparum infections in co-endemic regions, there is a strong argument for broadening current radical cure policy to include the administration of hypnozoitocidal doses of primaquine to patients with Plasmodium falciparum malaria. The most important reservoir for P. vivax transmission is likely to be very low-density, asymptomatic infections, the majority of which will arise from liver-stage relapses. Therefore, judicious mass administration of hypnozoitocidal therapy will reduce transmission of P. vivax to a greater extent than strategies focused on treatment of symptomatic patients. An efficacious hypnozoitocidal agent with a short curative treatment course would be particularly useful in mass drug administration campaigns.

  4. Root Canal Irrigation: Chemical Agents and Plant Extracts Against Enterococcus faecalis

    PubMed Central

    Borzini, Letizia; Condò, Roberta; De Dominicis, Paolo; Casaglia, Adriano; Cerroni, Loredana

    2016-01-01

    Background: There are various microorganisms related to intra and extra-radicular infections and many of these are involved in persistent infections. Bacterial elimination from the root canal is achieved by means of the mechanical action of instruments and irrigation as well as the antibacterial effects of the irrigating solutions. Enterococcus faecalis can frequently be isolated from root canals in cases of failed root canal treatments. Antimicrobial agents have often been developed and optimized for their activity against endodontic bacteria. An ideal root canal irrigant should be biocompatible, because of its close contact with the periodontal tissues during endodontic treatment. Sodium hypoclorite (NaOCl) is one of the most widely recommended and used endodontic irrigants but it is highly toxic to periapical tissues. Objectives: To analyze the literature on the chemotherapeutic agent and plant extracts studied as root canal irrigants. In particularly, the study is focused on their effect on Enterococcus faecalis. Method: Literature search was performed electronically in PubMed (PubMed Central, MEDLINE) for articles published in English from 1982 to April 2015. The searched keywords were “endodontic irrigants” and “Enterococcus faecalis” and “essential oil” and “plant extracts”. Results: Many of the studied chemotherapeutic agents and plant extracts have shown promising results in vitro. Conclusion: Some of the considered phytotherapic substances, could be a potential alternative to NaOCl for the biomechanical treatment of the endodontic space. PMID:28217184

  5. Neonatal behavioral assessment scale as a biomarker of the effects of environmental agents on the newborn

    SciTech Connect

    Tronick, E.Z.

    1987-10-01

    The organization of the newborn's brain and the nature of the effects of toxins and pollutants conspire to produce complex and difficult problems for the assessment of the behavioral effects of environmental agents. The newborn's brain can be characterized as relatively undifferentiated, and more vulnerable to, but potentially more capable of recovery from, the effects of environmental agents specific to this time period than it will be later in development. Environmental agents tend to have nonspecific, possibly subtle, effects that invade many areas of newborn functioning. These characteristics of the newborn and the behavioral effects of teratogens make assessment at this point in development difficult. Further exacerbating this difficulty is the nature of development. Development is critically dependent on the care the newborn receives. Distortions of a newborn's behavior can produce disturbances in the caretaking environment, and these caretaking disturbances can amplify the original behavioral distortion and produce other distortions. Attention to these types of effects must be built into an assessment. These considerations lead to the conclusion that an apical assessment of newborn behavior is required. The most standardized, valid, and reliable instrument currently available is the Neonatal Behavioral Assessment Scale developed by Brazelton. It assesses the integrated actions of the infant that function to regulate simultaneously the infant's internal state and exchanges with the animate (caretaking) and inanimate environment. The scale uses a set of reflex and behavioral items to assess the critical domains of infant functioning (e.g., the infant's ability to control his states of consciousness). 52 references.

  6. Alterations of chemotherapeutic pharmacokinetic profiles by drug–drug interactions

    PubMed Central

    Ghalib, Mohammed; Chaudhary, Imran; Goel, Sanjay

    2012-01-01

    Background Drug interactions in oncology are common place and largely ignored as we tolerate high thresholds of ‘toxic’ drug responses in these patients. However, in the era of ‘targeted’ or seemingly ‘less toxic’ therapy, these interactions are more commonly flagged and contribute significantly towards poor ‘quality of life’ and medical fatalities. Objective This review and opinion article focuses on alteration of chemotherapeutic pharmacokinetic profiles by drug interactions in the setting of polypharmacy. The assumption is that the drugs, with changes in their pharmacokinetics, will contribute towards changes in their pharmacodynamics. Methods The examples cited for such drug–drug interactions are culled from published literature with an emphasis on those interactions that have been well characterized at the molecular level. Results Although very few drug interaction studies have been performed on approved oncology based drugs, it is clear that drugs whose pharmacokinetics profiles are closely related to their pharmacodynamics will indeed result in clinically important drug interactions. Some newer mechanisms are described that involve interactions at the level of gene transcription, whereby, drug metabolism is significantly altered. However, for any given drug interaction, there does not seem to be a comprehensive model describing interactions. Conclusions Mechanisms based drug interactions are plentiful in oncology; however, there is an absolute lack of a comprehensive model that would predict drug–drug interactions. PMID:19239394

  7. Mesoscopic Effects in an Agent-Based Bargaining Model in Regular Lattices

    PubMed Central

    Poza, David J.; Santos, José I.; Galán, José M.; López-Paredes, Adolfo

    2011-01-01

    The effect of spatial structure has been proved very relevant in repeated games. In this work we propose an agent based model where a fixed finite population of tagged agents play iteratively the Nash demand game in a regular lattice. The model extends the multiagent bargaining model by Axtell, Epstein and Young [1] modifying the assumption of global interaction. Each agent is endowed with a memory and plays the best reply against the opponent's most frequent demand. We focus our analysis on the transient dynamics of the system, studying by computer simulation the set of states in which the system spends a considerable fraction of the time. The results show that all the possible persistent regimes in the global interaction model can also be observed in this spatial version. We also find that the mesoscopic properties of the interaction networks that the spatial distribution induces in the model have a significant impact on the diffusion of strategies, and can lead to new persistent regimes different from those found in previous research. In particular, community structure in the intratype interaction networks may cause that communities reach different persistent regimes as a consequence of the hindering diffusion effect of fluctuating agents at their borders. PMID:21408019

  8. Comparing the effects of manual therapy versus electrophysical agents in the management of knee osteoarthritis.

    PubMed

    Ali, Syed Shahzad; Ahmed, Syed Imran; Khan, Muhammad; Soomro, Rabail Rani

    2014-07-01

    To evaluate the effectiveness of Manual Therapy in comparison to Electrophysical agents in Knee Osteoarthritis. Total 50 patients with knee osteoarthritis were recruited from OPD of orthopedics civil hospital and Institute Of Physical Medicine & Rehabilitation, Dow University of Health Sciences Karachi. All those patients who fulfilled inclusion criteria were selected on voluntary basis. Selected patients were equally divided and randomly assigned into two groups with age and gender matching. The Manual therapy group received program of Maitland joint mobilization whereas Electrophysical Agent group received a program of TENS and cold pack. Both group received a program of exercise therapy as well. Patients received 3 treatment sessions per week for 4 successive weeks. Clinical assessment was performed using WOMAC index at baseline and on 12th treatment session. Both study groups showed clinically and statistically considerable improvements in WOMAC index. However, Related 2 sample t-test showed better clinical results in Manual Therapy group (p = 0.000) than Electrophysical Agents group (p = 0.008). The mean improvement in total WOMAC index was relatively higher in Manual Therapy group (22.36 ± 13.91) than Electrophysical Agent group (9.72 ± 6.10). This study concluded that manual therapy is clinically more effective in decreasing pain, stiffness and improving physical function in knee osteoarthritis.

  9. Antioxidant effects of pH-regulating agents on the thermal deterioration of vegetable oils.

    PubMed

    Endo, Yasushi; Yamadera, Yuki; Tsukui, Takayuki

    2014-01-01

    pH-Regulating agents, such as sodium tartrate, disodium succinate, and trisodium citrate, were investigated for their antioxidant activities during the thermal deterioration of vegetable oils. Refined rapeseed and rice bran oils, supplemented with pH-regulating agents and α-tocopherol (0.1%) were heated at 180℃. After heating, acid values (AVs), carbonyl values (CVs), polar material contents, and color (absorbance at 420 nm) of each sample were measured. All pH-regulating agents gave rise to reduced AVs, CVs, and polar material contents of vegetable oils during heating relative to samples not containing a pHregulating agent. Rapeseed and rice bran oils supplemented with sodium tartrate showed the lowest AVs, CVs, polar material contents and absorbances at 420 nm after heating. Sodium tartrate not only retarded the hydrolysis, thermal oxidation, polymerization, and coloration of both oils while heating at high temperatures, but it also showed antioxidant activity at the supplementation level of 0.01%. The antioxidant activity of sodium tartrate was higher than that of α-tocopherol during the deterioration of vegetable oils. Sodium tartrate was particularly effective retarding hydrolysis while heating at high temperatures, resulting in increase of AVs of vegetable oils. Sodium tartrate is therefore expected to be an effective antioxidant for the thermal deterioration of fats and oils during deep-fat frying.

  10. Biological effects of a root conditioning agent for dentin surface modification in vitro

    PubMed Central

    Lee, Jue-Yeon; Seol, Yang-Jo; Park, Jang-Ryul; Park, Yoon-Jeong

    2010-01-01

    Purpose Connective tissue reattachment to periodontally damaged root surfaces is one of the most important goals of periodontal therapy. The aim of this study was to develop a root conditioning agent that can demineralize and detoxify the infected root surface. Methods Dentin slices obtained from human teeth were treated with a novel root planing agent for 2 minutes and then washed with phosphate-buffered saline. Smear layer removal and type I collagen exposure were observed by scanning electron microscopy (SEM) and type I collagen immunostaining, respectively. Cell attachment and lipopolysaccharides (LPS) removal demonstrated the efficiency of the root conditioning agent. Results SEM revealed that the smear layer was entirely removed and the dentinal tubules were opened by the experimental gel. Type I collagen was exposed on the surfaces of the dentin slices treated by the experimental gel, which were compared with dentin treated with other root planing agents. Dentin slices treated with the experimental gel showed the highest number of attached fibroblasts and flattened cell morphology. The agar diffusion assay demonstrated that the experimental gel also has effective antimicrobial activity. Escherichia coli LPS were effectively removed from well plates by the experimental gel. Conclusions These results demonstrated that this experimental gel is a useful tool for root conditioning of infected root surfaces and can also be applied for detoxification of ailing implant surface threads. PMID:21246015

  11. Effect of capping agent concentration on thermoluminescence and photoluminescence of copper-doped zinc sulfide nanoparticles.

    PubMed

    Wanjari, Lata; Bisen, D P; Brahme, Namita; Sahu, Ishwar Prasad; Sharma, Ravi

    2015-08-01

    Copper-doped zinc sulfide (ZnS:Cu) nanoparticles with varying concentrations of capping agent were prepared using a chemical route technique. These particles were characterized by scanning electron microscopy (SEM), transmission electron microscopy and X-ray diffraction (XRD). Optical absorption studies showed that the absorption edge shifted towards the blue region as the concentration of the capping agent increased. Using effective mass approximation, calculation of the nanoparticle size indicated that effective band gap energy increases with decreasing particle size. The thermoluminescence (TL) properties of sodium hexameta phosphate (SHMP)-passivated ZnS:Cu nanoparticles were investigated after UV irradiation at room temperature. The TL glow curve of capped ZnS:Cu showed variations in TL peak position and intensity with the change in capping agent concentration. The photoluminescence (PL) spectra of ZnS:Cu nanoparticles excited at 254 nm exhibited a broad green emission band peaking around 510 nm, which confirmed the characteristic feature of Zn(2+) as well as Cu(2+) ions as the luminescent centres in the lattice. The PL spectra of ZnS:Cu nanoparticles with increasing capping agent concentrations revealed that the emission becomes more intense and shifted towards shorter wavelengths as the sizes of the samples were reduced.

  12. Long-term exposure to estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells

    PubMed Central

    Chang, Yu-Wei

    2017-01-01

    Chemotherapy is the most common clinical option for treatment of breast cancer. However, the efficacy of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen responsive and the levels of ovarian estrogen vary among the breast cancer patients primarily between pre- and post-menopausal age. Whether this age-dependent variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is not known. Therefore, the objective of this study was to evaluate the effects of natural estrogen 17 beta-estradiol (E2) on the efficacy of chemotherapeutic drugs in breast cancer cells. Estrogen responsive MCF-7 and T47D breast cancer cells were long-term exposed to 100 pg/ml estrogen, and using these cells the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased sensitivities of doxorubicin and cisplatin in estrogen-exposed MCF-7 and T47D cells as compared to their respective control cells. Gene expression analysis of cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-aza-2-deoxycytidine and Trichostatin A prior to doxorubicin and cisplatin treatments. The 5-aza-2 deoxycytidine pre-treatment significantly decreased the estrogen-induced efficacy of doxorubicin and cisplatin, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In summary, the results of this study revealed that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the chemotherapy strategies for treatment of breast

  13. Influence of refractive index and molecular weight of alcohol agents on skin optical clearing effect

    NASA Astrophysics Data System (ADS)

    Mao, Zhongzhen; Zheng, Ying; Hu, Yating; Lu, Wei; Luo, Qingming; Zhu, Dan

    2007-02-01

    In order to discuss the relative factors affecting the optical clearing effect of agents on skin tissues, six hydroxy-terminated and saturated alcohols with different refractive index and molecular weight were chosen as the optical clearing agents (OCAs). After being treated by different OCAs, the change of transmitted intensity of porcine skins in vitro was measured by single integrating sphere system. The results showed the optical clearing effects of six OCAs, i.e., glycerol, PEG400, PEG200, 1,3-propylene glycol, 1,4-butanediol and 1-butanol, arranged in the descending order. Based on the above results, the refractive index and molecular weight was further discussed. The optical clearing effect of alcohols has been deduced to have negative correlation with refractive index (r=-0.608), but no correlation with molecular weight (r= 0.008).

  14. Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells.

    PubMed

    Tanimura, Susumu; Uchiyama, Aya; Watanabe, Kazushi; Yasunaga, Masahiro; Inada, Yoshiyuki; Kawabata, Takumi; Iwashita, Ken-Ichi; Noda, Sinji; Ozaki, Kei-Ichi; Kohno, Michiaki

    2009-01-16

    The extracellular signal-regulated kinase (ERK) signaling pathway is constitutively activated in many human tumor cell types. Given the cytoprotective role of this pathway, we examined whether its specific blockade might sensitize human tumor cells to the induction of apoptosis by various anticancer drugs. Although blockade of ERK signaling alone did not induce substantial cell death, it resulted in marked and selective enhancement of the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the ERK pathway is constitutively activated. The synergistic activation of c-Jun NH(2)-terminal kinase by the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent appeared to be responsible, at least in part, for this effect. These results suggest that administration of the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent is a potential chemotherapeutic strategy for the treatment of tumor cells with constitutive activation of the ERK pathway.

  15. Remarkable shrinkage of sarcomatoid renal cell carcinoma with single-agent gemcitabine.

    PubMed

    Fujiwara, Yoshiro; Kiura, Katsuyuki; Tabata, Masahiro; Takigawa, Nagio; Hotta, Katsuyuki; Umemura, Shigeki; Omori, Masako; Gemba, Kenichi; Ueoka, Hiroshi; Tanimoto, Mitsune

    2008-04-01

    A 60-year-old Japanese man presented to our hospital with a painful left hip. Computed tomography showed a tumor in the left kidney and metastases in the left gluteus maximus muscle and lung. The pathological diagnosis of a biopsy specimen obtained from a metastatic lesion in the left gluteus maximus muscle was sarcomatoid renal cell carcinoma. On admission, his general condition was extremely poor. He was confined to bed because of severe left hip pain and confusion, possibly caused by hypercalcemia. This seriously ill patient suffering from advanced sarcomatoid renal cell carcinoma was treated with single-agent gemcitabine, resulting in symptom relief and a dramatic improvement in his status; all of the tumors had regressed significantly by the 11th dose of gemcitabine. These findings indicate that single-agent gemcitabine is one of the few chemotherapeutic agents effective for palliation in patients with sarcomatoid renal cell carcinoma, even those with poor performance status.

  16. [Effects of nootropic agents on visual functions and lacrimal antioxidative activity in patients with primary open-angle glaucoma].

    PubMed

    Davydova, N G; Kuznetsova, T P; Borisova, S A; Abdulkadyrova, M Zh

    2006-01-01

    The paper presents the results of an investigation of the effect of the nootropic agents pantogam and nooclerine on visual functions in patients with primary open-angle glaucoma. These agents have been found to have a beneficial effect on the functional activity of the retina and optic nerve, light sensitivity, hemo- and hydrodynamics of the eye.

  17. Multi-agent systems: effective approach for cancer care information management.

    PubMed

    Mohammadzadeh, Niloofar; Safdari, Reza; Rahimi, Azin

    2013-01-01

    Physicians, in order to study the causes of cancer, detect cancer earlier, prevent or determine the effectiveness of treatment, and specify the reasons for the treatment ineffectiveness, need to access accurate, comprehensive, and timely cancer data. The cancer care environment has become more complex because of the need for coordination and communication among health care professionals with different skills in a variety of roles and the existence of large amounts of data with various formats. The goals of health care systems in such a complex environment are correct health data management, providing appropriate information needs of users to enhance the integrity and quality of health care, timely access to accurate information and reducing medical errors. These roles in new systems with use of agents efficiently perform well. Because of the potential capability of agent systems to solve complex and dynamic health problems, health care system, in order to gain full advantage of E- health, steps must be taken to make use of this technology. Multi-agent systems have effective roles in health service quality improvement especially in telemedicine, emergency situations and management of chronic diseases such as cancer. In the design and implementation of agent based systems, planning items such as information confidentiality and privacy, architecture, communication standards, ethical and legal aspects, identification opportunities and barriers should be considered. It should be noted that usage of agent systems only with a technical view is associated with many problems such as lack of user acceptance. The aim of this commentary is to survey applications, opportunities and barriers of this new artificial intelligence tool for cancer care information as an approach to improve cancer care management.

  18. [Effects of plant polysaccharide compound agents on the photosynthetic characteristics and dry matter of soybean].

    PubMed

    Bai, Wen-Bo; Song, Ji-Qing; Guo, Jin-Yi; Liu, Xing-Hai; Li, Ji-Hui

    2012-07-01

    A field experiment was conducted to study the effects of foliar spraying three compound agents [plant polysaccharides (P1), plant polysaccharides and 5-aminolevulinic acid (P2), and plant polysaccharides and 5-aminolevulinic acid and dimethylpiperidinium chloride (P3)] at the initial flowering stage of soybean on its leaf chlorophyll content, photosynthesis and transpiration, dry matter accumulation and allocation, and grain yield. Within 35 days after spraying the three compound agents, the leaf chlorophyll content had obvious increase, and its decreasing trend with plant growth had somewhat delay. Compared with the control, spraying P1 and P3 increased the leaf photosynthetic rate and water use efficiency by more than 13.2% and 10.3%, respectively. With the spraying of the three compound agents, the dry matter accumulation in aerial part increased, and the allocation of dry matter from leaf to pod was also enhanced, with the contribution of post-anthesis assimilates to grain yield increased by more than 17.1%. The 100-grain mass and the pods and seeds per plant increased significantly after spraying P1 and P3, but had no significant increase after spraying P2. The grain yield of soybean treated with the three compound agents increased by more than 5.9%, compared with the control. This study showed that the three plant polysaccharide compound agents could increase the leaf chlorophyll content, delay the leaf-senescence, improve the leaf photosynthetic capacity and water status, effectively control the dry matter accumulation and post-anthesis assimilates allocation, and increase the grain yield of soybean.

  19. Effect of solubilizing agents on mupirocin loading into and release from PEGylated nanoliposomes.

    PubMed

    Cern, Ahuva; Nativ-Roth, Einat; Goldblum, Amiram; Barenholz, Yechezkel

    2014-07-01

    Mupirocin was identified by quantitative structure property relationship models as a good candidate for remote liposomal loading. Mupirocin is an antibiotic that is currently restricted to topical administration because of rapid hydrolysis in vivo to its inactive metabolite. Formulating mupirocin in PEGylated nanoliposomes may potentially expand its use to parenteral administration by protecting it from degradation in the circulation and target it (by the enhanced permeability effect) to the infected tissue. Mupirocin is slightly soluble in aqueous medium and its solubility can be increased using solubilizing agents. The effect of the solubilizing agents on mupirocin remote loading was studied when the solubilizing agents were added to the drug loading solution. Propylene glycol was found to increase mupirocin loading, whereas polyethylene glycol 400 showed no effect. Hydroxypropyl-β-cyclodextrin (HPCD) showed a concentration-dependent effect on mupirocin loading; using the optimal HPCD concentration increased loading, but higher concentrations inhibited it. The inclusion of HPCD in the liposome aqueous phase while forming the liposomes resulted in increased drug loading and substantially inhibited drug release in serum.

  20. Metallic taste as a side effect of topical fluorouracil use.

    PubMed

    Han, Sandra Y; Youker, Summer

    2011-10-01

    Topical fluorouracil is widely used for the treatment of precancerous and cancerous lesions of the skin. The most common side effect of this medication is localized irritant dermatitis. The authors report a case of dysgeusia with metallic taste as a side effect of this medication. While not previously seen with topical use, this is not an uncommon side effect seen with systemic administration of 5-fluorouracil. The etiology of dysgeusia from chemotherapeutic agents and systemic absorption of fluorouracil is discussed.

  1. Carbamide peroxide bleaching agents: effects on surface roughness of enamel, composite and porcelain.

    PubMed

    Moraes, R R; Marimon, J L M; Schneider, L F J; Correr Sobrinho, L; Camacho, G B; Bueno, M

    2006-03-01

    This study examined the effect of 10 and 35% carbamide peroxide bleaching agents on the surface roughness of enamel, feldspathic porcelain, and microfilled and microhybrid composite resins. Standardized cylindrical specimens were prepared for restorative materials. Enamel samples were obtained from buccal and lingual surfaces of human molars. Samples from each substrate were divided in three subgroups (n=10), according to surface treatment: distilled water (control), and 10 and 35% carbamide peroxide. The 10% agent was applied 3 h daily and the 35% agent was applied for 30 min/week, at 37 degrees C, during 21 days. Control samples remained stored in distilled water, at 37 degrees C. Roughness measurements (Ra, microm) were made at 24 h and repeated after 7, 14 and 21 days of exposure. Data were analyzed using ANOVA (split-plot design) and Tukey's test (5% significance level). Samples from control groups showed no significant alteration during all test periods, while for exposure to 10% agent, only the porcelain presented a rougher surface after 21 days (p<0.05). For the 35% product, roughness means significantly increased during the first and second weeks for enamel (p<0.05), and after 21 days for porcelain (p<0.05) and for the microhybrid composite (p<0.05). Microfilled samples showed no significant alteration throughout the 21-day period, regardless of the surface treatment.

  2. Getting along or ahead: Effects of gender identity threat on communal and agentic self-presentations.

    PubMed

    Sinclair, Samantha; Carlsson, Rickard; Björklund, Fredrik

    2016-10-01

    When faced with a threat to gender identity, people may try to restore their gender status by acting in a more gender-typical manner. The present research investigated effects of gender identity threat on self-presentations of agentic and communal traits in a Swedish and an Argentine sample (N = 242). Under threat (vs. affirmation), Swedish women deemphasized agentic traits (d [95% CI] = -0.41 [-0.93, 0.11]), Argentine women increased their emphasis on communal traits (d = 0.44 [-0.08, 0.97]), and Argentine men increased their emphasis on agentic traits (d = 0.49 [-0.03, 1.01]). However, Swedish men did not appear to be affected by the threat regarding agentic (d = 0.04 [-0.47, 0.55]) or communal traits (d = 0.23 [-0.29, 0.74]). The findings are to be considered tentative. Implications for identity threat research are discussed.

  3. An in vitro evaluation of the effects of desensitizing agents on microleakage of Class V cavities

    PubMed Central

    Yikilgan, İhsan; Özcan, Suat; Bala, Oya; Ömürlü, Hüma

    2016-01-01

    Background The aim of this study was to evaluate the effect of a desensitizing agent on microleakage of Class V cavities. Material and Methods 72 premolar teeth were used. There were 6 groups. Class V restorations were prepared with two different restorative materials (Equia fil, GC, America and Grandio, VOCO, Germany) and two adhesive systems (Clearfil SE Bond, Kuraray, Japan and S3 Bond Plus, Kuraray, Japan) with and without desensitizing agent (Gluma Desensitizer, Heraeus Kulzer, Germany). Restorations were polished with aluminum oxide abrasive discs. Then a range of 5 - 55C thermocycling was performed 10.000 times. The microleakage of restorations was examined with dye penetration method (Basic fuchsine). Bonferroni corrections and Kruskal-Wallis test were used to determine the significance of differences in occlusal and gingival dye penetration scores between groups. Results There was no stastistical significance between the occlusal and gingival microleakage scores within the groups were shown. Conclusions It can be concluded that use of desensitizing agent under both high viscosity glass ionomer restorative materials and resin composites doesn’t affect the microleakage. Key words:High viscosity glass ionomer cement, composite resin, desensitizing agent, microleakage. PMID:26855707

  4. Effects of biradical deuteration on the performance of DNP: Towards better performing polarizing agents

    DOE PAGES

    Perras, Frédéric A.; Reinig, Regina R.; Slowing, Igor I.; ...

    2015-11-20

    We study the effects of the deuteration of biradical polarizing agents on the efficiency of dynamic nuclear polarization (DNP) via the cross-effect. To this end, we synthesized a series of bTbK and TOTAPol biradicals with systematically increased deuterium substitution. The deuteration increases the radicals' relaxation time, thus contributing to a higher saturation factor and larger DNP enhancement, and reduces the pool of protons within the so-called spin diffusion barrier. Notably, we report that full or partial deuteration leads to improved DNP enhancement factors in standard samples, but also slows down the build-up of hyperpolarization. Improvements in DNP enhancements factors ofmore » up to 70% and time savings of up to 38% are obtained upon full deuteration. As a result, it is foreseen that this approach may be applied to other DNP polarizing agents thus enabling further sensitivity improvements.« less

  5. Effects of biradical deuteration on the performance of DNP: Towards better performing polarizing agents

    SciTech Connect

    Perras, Frédéric A.; Reinig, Regina R.; Slowing, Igor I.; Sadow, Aaron D.; Pruski, Marek

    2015-11-20

    We study the effects of the deuteration of biradical polarizing agents on the efficiency of dynamic nuclear polarization (DNP) via the cross-effect. To this end, we synthesized a series of bTbK and TOTAPol biradicals with systematically increased deuterium substitution. The deuteration increases the radicals' relaxation time, thus contributing to a higher saturation factor and larger DNP enhancement, and reduces the pool of protons within the so-called spin diffusion barrier. Notably, we report that full or partial deuteration leads to improved DNP enhancement factors in standard samples, but also slows down the build-up of hyperpolarization. Improvements in DNP enhancements factors of up to 70% and time savings of up to 38% are obtained upon full deuteration. As a result, it is foreseen that this approach may be applied to other DNP polarizing agents thus enabling further sensitivity improvements.

  6. Effects of temperature and chelating agents on cadmium uptake in the American oyster

    SciTech Connect

    Hung, Y.W.

    1982-05-01

    The effect of temperature on cadmium accumulations was evaluated in the tissue of the American oyster, Crassostrea virginica, under controlled laboratory conditions. Oysters have been reported to accumulate cadmium from seawater containing added cadmium chloride. However, the chemical form of cadmium in seawater has not been defined. This may profoundly influence the mechanism of uptake. Therefore, the report is also concerned with the effect of chelating agents on the uptake of cadmium. Chelating agents used were nitrilotriacetic acid, ethylene diaminetetraacetic acid and humic acid. At the end of a 40-day exposure to cadmium, 15 oysters were randomly selected from each tank of synthetic seawater, and each was dissected into 5 fractions, namely gills, mantle, adductor muscle, hepatopancreas and the remainder. The cadmium content of each fraction was analyzed by atomic absorption spectrophotometry with a flameless graphite furnace. (JMT)

  7. Effects of ganglion blocking agents on nicotine extensor convulsions and lethality in mice

    PubMed Central

    Aceto, M. D.; Bentley, H. C.; Dembinski, J. R.

    1969-01-01

    1. The ganglion blocking agents, chlorisondamine, pentamethonium, mecamylamine, decamethonium and hexamethonium all block nicotine extensor convulsions when administered intraventricularly in mice. Tetraethylammonium was inactive. 2. For the intraventricular route, there is a relationship between ganglionic blocking potency and blocking of nicotine extensor convulsions. Indirect evidence suggests that the site(s) of action of nicotine extensor convulsions and lethality is central in origin and associated with brain areas near the ventricles. 3. When ganglion blocking agents are given orally, subcutaneously or intravenously varying degrees of protection can be observed probably depending on factors such as whether or not the drugs cross the blood-brain barrier, absorption, etc., and the effectiveness in protecting mice from nicotine is not related to ganglionic blocking potency. 4. Atropine and morphine given intraventricularly or subcutaneously did not protect mice from the LD95 of nicotine. Chlorpromazine gave very erratic results and phenobarbitone was effective subcutaneously and to a lesser extent intraventricularly. PMID:4390479

  8. Weight-reducing side effects of the antiepileptic agents topiramate and zonisamide.

    PubMed

    Antel, J; Hebebrand, J

    2012-01-01

    Drug-induced weight alteration can be a serious side effect that applies to several therapeutic agents and must be referred to in the respective approved labeling texts. The side effect may become health threatening in case of significant weight change in either direction. Several antiepileptic drugs (AEDs) are associated with weight gain such as gabapentin, pregabalin, valproic acid, and vigabatrin and to some extent carbamazepine. Others are weight neutral such as lamotrigine, levetiracetam, and phenytoin or associated with slight weight loss as, e.g., felbamate. The focus of this chapter is on the two AEDs causing strong weight loss: topiramate and zonisamide. For both drugs, several molecular mechanisms of actions are published. We provide a review of these potential mechanisms, some of which are based on in vivo studies in animal models for obesity, and of clinical studies exploring these two drugs as single entities or in combinations with other agents.

  9. Inhibition of hydrogen sulfide biosynthesis sensitizes lung adenocarcinoma to chemotherapeutic drugs by inhibiting mitochondrial DNA repair and suppressing cellular bioenergetics

    PubMed Central

    Szczesny, Bartosz; Marcatti, Michela; Zatarain, John R.; Druzhyna, Nadiya; Wiktorowicz, John E.; Nagy, Péter; Hellmich, Mark R.; Szabo, Csaba

    2016-01-01

    Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H2S) has recently been proposed as a novel targeted anticancer approach. Here we show that human lung adenocarcinoma tissue expresses high levels of hydrogen sulfide (H2S) producing enzymes, namely, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), in comparison to adjacent lung tissue. In cultured lung adenocarcinoma but not in normal lung epithelial cells elevated H2S stimulates mitochondrial DNA repair through sulfhydration of EXOG, which, in turn, promotes mitochondrial DNA repair complex assembly, thereby enhancing mitochondrial DNA repair capacity. In addition, inhibition of H2S-producing enzymes suppresses critical bioenergetics parameters in lung adenocarcinoma cells. Together, inhibition of H2S-producing enzymes sensitize lung adenocarcinoma cells to chemotherapeutic agents via induction of mitochondrial dysfunction as shown in in vitro and in vivo models, suggesting a novel mechanism to overcome tumor chemoresistance. PMID:27808278

  10. Effects of various pharmacological agents on the function of norepinephrine transporter.

    PubMed

    Satoh, Noriaki; Toyohira, Yumiko; Takahashi, Keita; Yanagihara, Nobuyuki

    2015-03-01

    The norepinephrine transporter is selectively expressed in noradrenergic nerve terminals, where it can exert spatial and temporal control over the action of norepinephrine. The norepinephrine transporter mediates the termination of neurotransmission via the reuptake of norepinephrine released into the extracellular milieu. In the present brief review, we report our recent studies about the effects of various pharmacological agents such as fasudil, nicotine, pentazocine, ketamine and genistein on norepinephrine transporter function.

  11. Effects of chemical and biological warfare remediation agents on the materials of museum objects

    NASA Astrophysics Data System (ADS)

    Solazzo, C.; Erhardt, D.; Marte, F.; von Endt, D.; Tumosa, C.

    In the fall of 2001, anthrax-contaminated letters were sent to public figures in the United States. Chemical and radiation treatments were employed to decontaminate exposed buildings, objects, and materials. These treatments are effective, but potentially damaging to exposed objects and materials. The recommended surface chemical treatments include solutions, gels, and foams of oxidizing agents such as peroxides or chlorine bleaching agents. Such oxidizing agents are effective against a wide range of hazardous chemical and biological agents. Knowing how these reagents affect various substrates would help to anticipate and to minimize any potential damage. We are examining the effects on typical museum materials of reagents likely to be used, including hydrogen peroxide, sodium hypochlorite, and potassium peroxymonosulfate. Results so far show significant changes in a number of materials. Surface corrosion was observed on metals such as copper, silver, iron, and brass. Color changes occurred with at least one reagent in about one-fourth of the dyed fabric swatches tested, and about half of the inks. Samples of aged yellowed paper are bleached. Effects varied with both the substrate and the tested reagent. The observed changes were generally less drastic than might have been expected. Enough materials were affected, though, to preclude the use of these reagents on museum objects unless no less drastic alternative is available. It appears that many objects of lesser intrinsic value can be treated without severe loss of properties or usefulness. For example, most documents should remain legible if the appropriate reagent is used. This work will provide a basis for determining which treatment is most appropriate for a specific situation and what consequences are to be expected from other treatments.

  12. Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri.

    PubMed

    Kim, Jong-Hyun; Jung, Suk-Yul; Lee, Yang-Jin; Song, Kyoung-Ju; Kwon, Daeho; Kim, Kyongmin; Park, Sun; Im, Kyung-Il; Shin, Ho-Joon

    2008-11-01

    Naegleria fowleri is a ubiquitous, pathogenic free-living amoeba; it is the most virulent Naegleria species and causes primary amoebic meningoencephalitis (PAME) in laboratory animals and humans. Although amphotericin B is currently the only agent available for the treatment of PAME, it is a very toxic antibiotic and may cause many adverse effects on other organs. In order to find other potentially therapeutic agents for N. fowleri infection, the present study was undertaken to evaluate the in vitro and in vivo efficacies of miltefosine and chlorpromazine against pathogenic N. fowleri. The result showed that the growth of the amoeba was effectively inhibited by treatment with amphotericin B, miltefosine, and chlorpromazine. When N. fowleri trophozoites were treated with amphotericin B, miltefosine, and chlorpromazine, the MICs of the drug were 0.78, 25, and 12.5 microg/ml, respectively, on day 2. In experimental meningoencephalitis of mice that is caused by N. fowleri, the survival rates of mice treated with amphotericin B, miltefosine, and chlorpromazine were 40, 55, and 75%, respectively, during 1 month. The average mean time to death for the amphotericin B, miltefosine, and chlorpromazine treatments was 17.9 days. In this study, the effect of drugs was found to be optimal when 20 mg/kg was administered three times on days 3, 7, and 11. Finally, chlorpromazine had the best therapeutic activity against N. fowleri in vitro and in vivo. Therefore, it may be a more useful therapeutic agent for the treatment of PAME than amphotericin B.

  13. Molecular and morphological surface analysis: effect of filling pastes and cleaning agents on root dentin

    PubMed Central

    DAINEZI, Vanessa Benetello; IWAMOTO, Alexsandra Shizue; MARTIN, Airton Abrahão; SOARES, Luís Eduardo Silva; HOSOYA, Yumiko; PASCON, Fernanda Miori; PUPPIN-RONTANI, Regina Maria

    2017-01-01

    Abstract The quality of the dentin root is the most important factor for restoration resin sealing and drives the outcome of endodontic treatment. Objective This study evaluated the effect of different filling pastes and cleaning agents on the root dentin of primary teeth using Fourier-transformed Raman spectroscopy (FT-Raman), micro energy-dispersive X-ray fluorescence (µ-EDXRF) and scanning electron microscopic (SEM) analysis. Material and Methods Eighty roots of primary teeth were endodontically prepared and distributed into 4 groups and filled according to the following filling pastes: Control-no filling (CP), Calen®+zinc oxide (CZ), Calcipex II® (CII), Vitapex® (V). After seven days, filling paste groups were distributed to 4 subgroups according to cleaning agents (n=5): Control-no cleaning (C), Ethanol (E), Tergenform® (T), 35% Phosphoric acid (PA). Then, the roots were sectioned and the dentin root sections were internally evaluated by FT-Raman, µ-EDXRF and SEM. Data was submitted to two-way ANOVA and Tukey tests (α=0.05). Results Regarding filling pastes, there was no significant difference in organic content. CP provided the lowest calcium values and, calcium/phosphoric ratio (Ca/P), and the highest phosphoric values. For cleaning agents there was no difference in organic content when compared to the C; however, T showed significantly higher calcium and Ca/P than PA. All groups showed similar results for phosphorus. The dentin smear layer was present after use of the cleaning agents, except PA. Conclusion The filling pastes changed the inorganic content, however they did not change the organic content. Cleaning agents did not alter the inorganic and organic content. PA cleaned and opened dentin tubules. PMID:28198982

  14. Evaluation of antibacterial effects of pulp capping agents with direct contact test method

    PubMed Central

    Yalcin, Muhammet; Arslan, Ugur; Dundar, Ayse

    2014-01-01

    Objectives: Calcium hydroxide has been used in dentistry as a major capping material having the capacity to introduce the formation of a mineralized dentin bridge, but it has no direct inducing effect to the pulp cells. The purpose of this study was to evaluate the antibacterial properties of three different pulp capping agents using a direct contact test (DCT). Materials and Methods: The antibacterial properties of three pulp capping agents were evaluated a DCT. For the DCT, wells (n = 12) of 96-microtiter plates were coated with the tested cements (Dycal, Dentsply, USA; DiaRoot BioAggregate, Diadent, Holland; Calcimol LC, Voco, Germany) and Kalzinol (zinc oxide/eugenol cement, Dentsply, USA) was used as control material. A Lactobacillus casei suspension was placed on the surface of each specimen for 1 h at 37°C. Bacterial growth was monitored for 16 h with a temperature-controlled microplate spectrophotometer. The kinetics of the outgrowth in each well were recorded continuously at 650 nm every 30 min. The data were analyzed by one-way ANOVA, and Tamhane's T2 multiple comparison test. The level of significance was determined as P < 0.05. Results: All pulp capping agents showed an increase in the logarithmic growth rate of L. casei when compared with the control group (P < 0.05). Therefore, all pulp capping agents did not show antibacterial activity. Conclusions: The tested pulp capping agents haven't got antibacterial properties. Therefore, they should be used carefully when pulp is exposed or only very thin dentin remained over the pulp to avoid bacterial contamination. PMID:24966754

  15. The Effectiveness of Physical Agents for Lower-Limb Soft Tissue Injuries: A Systematic Review.

    PubMed

    Yu, Hainan; Randhawa, Kristi; Côté, Pierre; Optima Collaboration

    2016-07-01

    Study Design Systematic review. Background Soft tissue injuries to the lower limb bring a substantial health and economic burden to society. Physical agents are commonly used to treat these injuries. However, the effectiveness of many such physical agents is not clearly established in the literature. Objective To evaluate the effectiveness and safety of physical agents for soft tissue injuries of the lower limb. Methods We searched 5 databases from 1990 to 2015 for randomized controlled trials (RCTs), cohort studies, and case-control studies. Paired reviewers independently screened the retrieved literature and appraised relevant studies using the Scottish Intercollegiate Guidelines Network criteria. Studies with a high risk of bias were excluded. We synthesized low-risk-of-bias studies according to principles of best-evidence synthesis. Results We screened 10261 articles. Of 43 RCTs identified, 20 had a high risk of bias and were excluded from the analysis, and 23 RCTs had a low risk of bias and were included in the analysis. The available higher-quality evidence suggests that patients with persistent plantar fasciitis may benefit from ultrasound or foot orthoses, while those with persistent midportion Achilles tendinopathy may benefit from shockwave therapy. However, the current evidence does not support the use of shockwave therapy for recent plantar fasciitis, low-Dye taping for persistent plantar fasciitis, low-level laser therapy for recent ankle sprains, or splints for persistent midportion Achilles tendinopathy. Finally, evidence on the effectiveness of the following interventions is not established in the current literature: (1) shockwave therapy for persistent plantar fasciitis, (2) cryotherapy or assistive devices for recent ankle sprains, (3) braces for persistent midportion Achilles tendinopathy, and (4) taping or electric muscle stimulation for patellofemoral pain syndrome. Conclusion Almost half the identified RCTs that evaluated the effectiveness of

  16. Neurotransmitter-blocking agents influence antinociceptive effects of carbamazepine, baclofen, pentazocine and morphine on bradykinin-induced trigeminal pain.

    PubMed

    Foong, F W; Satoh, M

    1984-06-01

    The influence of naloxone (a narcotic antagonist), bicuculline (a GABA antagonist), phentolamine (an alpha-blocking agent), propranolol (a beta-adrenergic blocking agent), haloperidol (a dopaminergic blocking agent), methysergide (a serotonergic blocking agent) and atropine (a muscarinic blocking agent), on the antinociceptive effects induced by carbamazepine, baclofen, pentazocine and morphine, were investigated with a new antinociception test, using the trigeminal pain induced by application of bradykinin onto the tooth pulp of the rat. The antinociceptive effect of carbamazepine was significantly inhibited by bicuculline, phentolamine, propranolol and haloperidol but not by naloxone, methysergide and atropine. The effect of baclofen was significantly reduced by naloxone, bicuculline, propranolol and atropine but not by phentolamine, haloperidol and methysergide. The antinociceptive actions of pentazocine and morphine on trigeminal pain were significantly reduced by naloxone and phentolamine, and by naloxone alone, respectively. These results suggest the involvement of different neurotransmitters in the antinociceptive effects of the four analgesic drugs on trigeminal pain induced by bradykinin.

  17. The effects of physical therapeutic agents on serum levels of stress hormones in patients with osteoarthritis

    PubMed Central

    Tönük, Şükrü Burak; Serin, Erdinc; Ayhan, Fikriye Figen; Yorgancioglu, Zeynep Rezan

    2016-01-01

    Abstract To investigate the effects of physical agents on the levels of stress hormones in patients with osteoarthritis (OA). Transcutaneous electrical nerve stimulation, hot packs, and therapeutic ultrasound were applied to the lumbar region and knees of patients with OA. Blood samples were taken for the measurement of the serum levels of glucose, insulin (INS), growth hormone (GH), prolactin (PRL), cortisol (COR), and plasma adrenocorticotropic hormone (ACTH) immediately before and after the 1st session, to investigate the acute effects of those physical agents on the endocrine system. The hormone levels were also measured every 5 sessions in a total of 10 sessions. The treatment response was also evaluated by using the visual analogue scale (VAS), Roland Morris Disability Questionnaire (RMDQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) throughout the therapy period. After the 1st session, there was a decrease in INS levels and a mild decrease in PRL levels (P = 0.001 and P < 0.05, respectively). Throughout the 10-session therapy period, the INS levels increased, whereas the ACTH and COR levels decreased (P < 0.05 for all). The VAS-spine, RMDQ, VAS-knee, and WOMAC scores decreased (P = 0.001 for VAS-spine and P < 0.001 for all others). A positive correlation was detected between the changes in serum COR and WOMAC-pain score (P < 0.05). Although the combination therapy caused changes in INS level accompanied with steady glucose levels, the application of physical agents did not adversely affect the hormone levels. The decrease in ACTH and COR levels may be attributed to the analgesic effect of agents and may be an indicator of patient comfort through a central action. PMID:27583888

  18. Effects of insulin and other antihyperglycaemic agents on lipid profiles of patients with diabetes.

    PubMed

    Chaudhuri, A; Dandona, P

    2011-10-01

    Increased morbidity and mortality risk due to diabetes-associated cardiovascular diseases is partly associated with hyperglycaemia as well as dyslipidaemia. Pharmacological treatment of diabetic hyperglycaemia involves the use of the older oral antidiabetic drugs [OADs: biguanides, sulphonylureas (SUs), α-glucosidase inhibitors and thiazolidinediones], insulin (human and analogues) and/or incretin-based therapies (glucagon-like peptide-1 analogues and dipeptidyl peptidase 4 inhibitors). Many of these agents have also been suggested to improve lipid profiles in patients with diabetes. These effects may have benefits on cardiovascular risk beyond glucose-lowering actions. This review discusses the effects of OADs, insulins and incretin-based therapies on lipid variables along with the possible mechanisms and clinical implications of these findings. The effects of intensive versus conventional antihyperglycaemic therapy on cardiovascular outcomes and lipid profiles are also discussed. A major conclusion of this review is that agents within the same class of OADs can have different effects on lipid variables and that contrary to the findings in experimental models, insulin has been shown to have beneficial effects on lipid variables in clinical trials. Further studies are needed to understand the precise effect and the mechanisms of these effects of insulin on lipids.

  19. Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-EGFR] in Dual-combination with Epirubicin-(C3-amide)-[anti-HER2/neu] against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3) and the Complementary Effect of Mebendazole

    PubMed Central

    Coyne, CP; Jones, Toni; Bear, Ryan

    2015-01-01

    Aims Delineate the feasibility of simultaneous, dual selective “targeted” chemotherapeutic delivery and determine if this molecular strategy can promote higher levels anti-neoplastic cytotoxicity than if only one covalent immunochemotherapeutic is selectively “targeted” for delivery at a single membrane associated receptor over-expressed by chemotherapeutic-resistant mammary adenocarcinoma. Methodology Gemcitabine and epirubicin were covalently bond to anti-EGFR and anti-HER2/neu utilizing a rapid multi-phase synthetic organic chemistry reaction scheme. Determination that 96% or greater gemcitabine or epirubicin content was covalently bond to immunoglobulin fractions following size separation by micro-scale column chromatography was established by methanol precipitation analysis. Residual binding-avidity of gemcitabine-(C4-amide)-[anti-EG-FR] applied in dual-combination with epirubicin-(C3-amide)-[anti-HER2/neu] was determined by cell-ELIZA utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) populations. Lack of fragmentation or polymerization was validated by SDS-PAGE/immunodetection/chemiluminescent autoradiography. Anti-neoplastic cytotoxic potency was determined by vitality stain analysis of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) monolayers known to uniquely over-express EGFR (2 × 105/cell) and HER2/neu (1 × 106/cell) receptor complexes. The covalent immunochemotherapeutics gemcitabine-(C4-amide)-[anti-EGFR] and epirubicin-(C3-amide)-[anti-HER2/neu] were applied simultaneously in dual-combination to determine their capacity to collectively evoke elevated levels of anti-neoplastic cytotoxicity. Lastly, the tubulin/microtubule inhibitor mebendazole evaluated to determine if it’s potential to complemented the anti-neoplastic cytotoxic properties of gemcitabine-(C4-amide)-[anti-EGFR] in dual-combination with epirubicin-(C3-amide)-[anti-HER2/neu]. Results Dual-combination of gemcitabine-(C4-amide)-[anti-EGFR] with

  20. Palladium nanosheets as highly stable and effective contrast agents for in vivo photoacoustic molecular imaging

    NASA Astrophysics Data System (ADS)

    Nie, Liming; Chen, Mei; Sun, Xiaolian; Rong, Pengfei; Zheng, Nanfeng; Chen, Xiaoyuan

    2014-01-01

    A stable and efficient contrast agent is highly desirable for photoacoustic (PA) imaging applications. Recently gold nanostructures have been widely reported and studied for PA imaging and photothermal therapy. However, the structures of the nonspherical gold nanoparticles are easily destroyed after laser irradiation and thus may fail to complete the intended tasks. In this study, we propose to apply palladium nanosheets (PNSs), with strong optical absorption in the near-infrared (NIR) region, as a new class of exogenous PA contrast agents. PA and ultrasound (US) images were acquired sequentially by a portable and fast photoacoustic tomography (PAT) system with a hand-held transducer. Significant and long-lasting imaging enhancement in SCC7 head and neck squamous cell carcinoma was successfully observed in mice by PAT over time after tail vein administration of PNSs. The morphology and functional perfusion of the tumors were delineated in PA images due to the nanoparticle accumulation. PAT of the main organs was also conducted ex vivo to trace the fate of PNSs, which was further validated by inductively coupled plasma atomic emission spectrometry (ICP-AES). No obvious toxic effect was observed by in vitro MTT assay and ex vivo histological examination 7 days after PNS administration. With the combination of a portable imaging instrument and signal specificity, PNSs might be applied as stable and effective agents for photoacoustic cancer detection, diagnosis and treatment guidance.

  1. Short cationic lipopeptides as effective antibacterial agents: Design, physicochemical properties and biological evaluation.

    PubMed

    Azmi, Fazren; Elliott, Alysha G; Marasini, Nirmal; Ramu, Soumya; Ziora, Zyta; Kavanagh, Angela M; Blaskovich, Mark A T; Cooper, Matthew A; Skwarczynski, Mariusz; Toth, Istvan

    2016-05-15

    The spread of drug-resistant bacteria has imparted a sense of urgency in the search for new antibiotics. In an effort to develop a new generation of antibacterial agents, we have designed de novo charged lipopeptides inspired by natural antimicrobial peptides. These short lipopeptides are composed of cationic lysine and hydrophobic lipoamino acids that replicate the amphiphilic properties of natural antimicrobial peptides. The resultant lipopeptides were found to self-assemble into nanoparticles. Some were effective against a variety of Gram-positive bacteria, including strains resistant to methicillin, daptomycin and/or vancomycin. The lipopeptides were not toxic to human kidney and liver cell lines and were highly resistant to tryptic degradation. Transmission electron microscopy analysis of bacteria cells treated with lipopeptide showed membrane-damage and lysis with extrusion of cytosolic contents. With such properties in mind, these lipopeptides have the potential to be developed as new antibacterial agents against drug-resistant Gram-positive bacteria.

  2. Effect of Complex Agent on Characteristics of Copper Conductive Pattern Formed by Ink-jet Printing

    NASA Astrophysics Data System (ADS)

    Lee, Young-In; Lee, Kun-Jae; Goo, Yong-Sung; Kim, Nam-Woo; Byun, Younghoon; Kim, Joong-Do; Yoo, Bongyoung; Choa, Yong-Ho

    2010-08-01

    In this study, Cu ion complex ink was successfully synthesized by a modified electrolysis method in which the Cu ions generated from bulk metal plates by an electric field were coordinated with complex agents. The synthesized ink was ink-jet-printed on a flexible substrate and converted to a dense Cu pattern after sintering at 250 °C. The pattern was characterized by X-ray diffractometry, field emission scanning electron microscope, and four-point probe method to confirm the crystal structure, microstructure, and electrical conductivity, respectively. The effect of the type of complex agent on the characteristics of a Cu conductive pattern was also determined using the analysis results. Finally, we conducted the direct writing of conductive dots and lines using the Cu ion complex ink, and confirmed that fine patterning for application in electronics is possible with the Cu ion complex ink.

  3. Concentration Effect of Reducing Agents on Green Synthesis of Gold Nanoparticles: Size, Morphology, and Growth Mechanism

    NASA Astrophysics Data System (ADS)

    Kim, Hyun-seok; Seo, Yu Seon; Kim, Kyeounghak; Han, Jeong Woo; Park, Youmie; Cho, Seonho

    2016-04-01

    Under various concentration conditions of reducing agents during the green synthesis of gold nanoparticles (AuNPs), we obtain the various geometry (morphology and size) of AuNPs that play a crucial role in their catalytic properties. Through both theoretical and experimental approaches, we studied the relationship between the concentration of reducing agent (caffeic acid) and the geometry of AuNPs. As the concentration of caffeic acid increases, the sizes of AuNPs were decreased due to the adsorption and stabilizing effect of oxidized caffeic acids (OXCAs). Thus, it turns out that optimal concentration exists for the desired geometry of AuNPs. Furthermore, we investigated the growth mechanism for the green synthesis of AuNPs. As the caffeic acid is added and adsorbed on the surface of AuNPs, the aggregation mechanism and surface free energy are changed and consequently resulted in the AuNPs of various geometry.

  4. Combination effect of recombinant human interleukin-1 alpha with antimicrobial agents.

    PubMed Central

    Nakamura, S; Minami, A; Fujimoto, K; Kojima, T

    1989-01-01

    Combination effects of recombinant human interleukin-1 alpha with ceftazidime, moxalactam, gentamicin, enoxacin, amphotericin B, miconazole, or an immunoglobulin preparation were evaluated in systemic infections with Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans in normal mice and systemic infection with P. aeruginosa in mice with leukopenia induced by preadministration of cyclophosphamide. Synergistic effects were generally observed at interleukin-1 alpha doses as low as 1 to 30 ng per mouse with most combinations. The results show the possibility that recombinant human interleukin-1 alpha could be of help for treating obstinate infections not successfully treated with antimicrobial agents alone. PMID:2589847

  5. EFFECTIVENESS OF HOME BLEACHING AGENTS IN DISCOLORED TEETH AND INFLUENCE ON ENAMEL MICROHARDNESS

    PubMed Central

    Delfino, Carina Sinclér; Chinelatti, Michelle Alexandra; Carrasco-Guerisoli, Laíse Daniela; Batista, Andrigo Reis; Fröner, Izabel Cristina; Palma-Dibb, Regina Guenka

    2009-01-01

    Objectives: This study evaluated the effectiveness of different home bleaching agents on color alteration and their influence on surface and subsurface microhardness of discolored bovine enamel. Material and Methods: Forty-five fragments of bovine incisors were randomly allocated into 3 groups (n=15) according to the bleaching agent: 10% carbamide peroxide gel (CP10), 16% carbamide peroxide gel (CP16) and 6.5%-hydrogen-peroxide-based strip (HP6.5). Before bleaching treatment, initial values of Knoop surface microhardness and color (CIEL*a*b*) were obtained and the fragments were artificially stained in hemolyzed rat blood. Then, bleaching treatments were performed over a 21-day period. Color changes (ΔE) were assessed at 7, 14 and 21 days, and final surface microhardness reading was done after 21 days. Thereafter, the fragments were bisected to obtain subsurface microhardness. Data were subjected to ANOVA and Tukey's tests (α=5%). Results: Color changes produced by CP16 were similar to those of CP10, and the color changes produced by these materials were significantly superior to those produced by HP6.5. Color changes at 21 days were superior to 7 days and similar to 14 days. The time did not influence color changes for CP16, which showed similarity between the 14- and 21-day results. No statistically significant differences were found among the home bleaching agents for surface and subsurface microhardness. Conclusions: Microhardness of bovine enamel was not affected by the bleaching agents. The 16% carbamide peroxide gel was the most effective for bleaching the stained substrate. PMID:19668986

  6. Release time of residual oxygen after dental bleaching with 35% hydrogen peroxide: effect of a catalase-based neutralizing agent.

    PubMed

    Guasso, Bárbara; Salomone, Paloma; Nascimento, Paulo Cícero; Pozzobon, Roselaine Terezinha

    2016-01-01

    This article assessed the effect of a catalase-based agent on residual oxygen (O2) release from teeth exposed to 35% hydrogen peroxide (H2O2). The use of the catalase-based neutralizer agent for 2-3 minutes was able to release residual O2 5 days after exposure to a 35% H2O2-based bleaching gel.

  7. Lipopolysaccharide a virulence factor of Helicobacter pylori: effect of antiulcer agents.

    PubMed

    Piotrowski, J

    1998-03-01

    Helicobacter pylori plays a major role in the pathogenesis of gastric disease. The gastric epithelial integrity is compromised by the H. pylori cell wall lipopolysaccharide untoward effect on the gastric epithelial cell receptors interaction with proteins of extracellular matrix, glycoproteins of mucus coat, and bioactive peptides. These interactions cause the weakening of the mucus coat rendering the underying epithelium vulnerable to noxious luminal contents and disrupting the regulatory feedback of somatostatin and gastrin. Moreover, H. pylori lipopolysaccharide induces histologic lesions typical of acute gastritis and these changes are reflected in the increased epithelial cell apoptosis. These findings thus identify cell wall lipopolysaccharide as a virulent factor responsible for the H. pylori effect on gastric epithelium. The effect of antiulcer agents on the interference of lipopolysaccharide with the laminin receptor was found to be most efficiently countered by ebrotidine, sulglycotide and sucralfate, whereas sulglycotide is the most potent in the reversal of the inhibitory effect of the lipopolysaccharide on mucin receptor binding. In the case of somatostatin-receptor binding, sulglycotide followed by sucralfate and ebrotidine showed the most potency in of reversing the effect of H. pylori lipopolysaccharide. Thus these antiulcer agents have a great promise in the treatment gastric diseases associated with H. pylori infection.

  8. Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells.

    PubMed

    Pédeboscq, Stéphane; L'Azou, Béatrice; Passagne, Isabelle; De Giorgi, Francesca; Ichas, François; Pometan, Jean-Paul; Cambar, Jean

    2008-01-01

    Glioblastoma is a malignant astrocytic tumor with a median survival of about 12 months for which new therapeutic strategies are required. We therefore examined the cytotoxicity of anticancer drugs with different mechanisms of action on two human glioblastoma cell lines expressing various levels of EGFR (epidermal growth factor receptor). Apoptosis induced by these anticancer agents was evaluated by flow cytometry. The cytotoxicity of alkylating drugs followed a dose-effect curve and cytotoxicity index values were lower with carboplatin than with BCNU and temozolomide. Anti-EGFR gefitinib (10 microM) cytotoxicity on DBTRG.05-MG expressing high levels of EGFR was significantly higher than on U87-MG expressing low levels of EGFR. Carboplatin and temozolomide cytotoxicity was potentiated with the addition of gefitinib on DBTRG.05-MG. Among the anticancer agents tested, the proteasome inhibitor bortezomib was the most cytotoxic with very low IC50 on the two cell lines. Moreover, all anticancer drugs tested induced apoptosis in a concentration-dependent manner. Bortezomib proved to be a more potent inductor of apoptosis than gefitinib and alkylating agents. These results show the efficacy of bortezomib and of the association between conventional chemotherapy and gefitinib on glioblastoma cells and therefore suggest the interest of these molecules in the treatment of glioblastoma.

  9. Effect of Ductile Agents on the Dynamic Behavior of SiC3D Network Composites

    NASA Astrophysics Data System (ADS)

    Zhu, Jingbo; Wang, Yangwei; Wang, Fuchi; Fan, Qunbo

    2016-10-01

    Co-continuous SiC ceramic composites using pure aluminum, epoxy, and polyurethane (PU) as ductile agents were developed. The dynamic mechanical behavior and failure mechanisms were investigated experimentally using the split Hopkinson pressure bar (SHPB) method and computationally by finite element (FE) simulations. The results show that the SiC3D/Al composite has the best overall performance in comparison with SiC3D/epoxy and SiC3D/PU composites. FE simulations are generally consistent with experimental data. These simulations provide valuable help in predicting mechanical strength and in interpreting the experimental results and failure mechanisms. They may be combined with micrographs for fracture characterizations of the composites. We found that interactions between the SiC phase and ductile agents under dynamic compression in the SHPB method are complex, and that interfacial condition is an important parameter that determines the mechanical response of SiC3D composites with a characteristic interlocking structure during dynamic compression. However, the effect of the mechanical properties of ductile agents on dynamic behavior of the composites is a second consideration in the production of the composites.

  10. Biocompatibility and Effectiveness Evaluation of a New Hemostatic Embolization Agent: Thrombin Loaded Alginate Calcium Microsphere

    PubMed Central

    Xuan, Fengqi; Rong, Jingjing; Liang, Ming; Zhang, Xuwen; Sun, Jingyang; Zhao, Lijun; Li, Yang; Liu, Dan; Li, Fei; Wang, Xiaozeng

    2017-01-01

    Background. Until now, there has been no ideal embolization agent for hemorrhage in interventional treatment. In this study, the thrombin was encapsulated in alginate calcium microsphere using electrostatic droplet technique to produce new embolization agent: thrombin loaded alginate calcium microspheres (TACMs). Objectives. The present work was to evaluate the biocompatibility and hemostatic efficiency of TACMs. Methods. Cell cytotoxicity, hemolysis, and superselective embolization of dog liver arteries were performed to investigate the biocompatibility of TACMs. To clarify the embolic effect of TACMs mixed thrombus in vivo, hepatic artery injury animal model of 6 beagles was established and transcatheter artery embolization for bleeding was performed. Results. Coculture with VECs revealed the noncytotoxicity of TACMs, and the hemolysis experiment was negligible. Moreover, the histological study of TACMs in liver blood vessel showed signs of a slight inflammatory reaction. The results of transcatheter application of TACMs mixed thrombus for bleeding showed that the blood flow was shut down completely after the TACMs mixed thrombus was delivered and the postprocedural survival rate of animal models at 12 weeks was 100%. Conclusions. With their good biocompatibility and superior hemostatic efficiency, TACMs might be a promising new hemostatic agent with a wide range of potential applications. PMID:28303245

  11. Effects of age, gender, and immunosuppressive agents on in vivo toll-like receptor pathway responses.

    PubMed

    Khan, Niamat; Summers, Colin W; Helbert, Matthew R; Arkwright, Peter D

    2010-04-01

    Toll-like receptors (TLRs) are important in the initiation of immune responses in both health and disease. How TLR activity alters with age, gender, and also with immunosuppressive agents is still largely unexplored. We studied TLR activity in 49 healthy individuals as well as in 26 patients receiving immunosuppressive drugs. TLR activity did not alter significantly between the ages of 2 and 67 years. However, females had twice the TLR7 ligand-induced interferon-I response of males (OR [95% CI] 2.7 [1.4-5.1]), whereas TLR3 and four activities were not significantly different between the sexes. The T-cell immunosuppressant agents cyclosporine, tacrolimus, and azathioprine, as well as low dose glucocorticosteroids did not significantly alter TLR pathway responses. In contrast, high dose glucocorticosteroids reduced in vivo TLR responses by 70%-90%. We suggest that gender differences in TLR responses may help to explain the female preponderance of some autoimmune disorders. Furthermore, an understanding the effects of immunosuppressive agents on TLR-pathway activity should allow more focused therapy for autoimmune disorders.

  12. Gaseous emissions in municipal wastes composting: effect of the bulking agent.

    PubMed

    Maulini-Duran, Caterina; Artola, Adriana; Font, Xavier; Sánchez, Antoni

    2014-11-01

    In this study, the emissions of volatile organic compounds (VOC), CH4, N2O and NH3 during composting non-source selected MSW, source selected organic fraction of municipal solid wastes (OFMSW) with wood chips as bulking agent (OF_wood) and source selected OFMSW with polyethylene (PE) tube as bulking agent (OF_tube) and the effect of bulking agent on these emissions have been systematically studied. Emission factors are provided (in kg compound Mg(-1) dry matter): OF_tube (CH4: 0.0185±0.004; N2O: 0.0211±0.005; NH3: 0.612±0.269; VOC: 0.688±0.082) and MSW (CH4: 0.0549±0.0171; N2O: 0.032±0.015; NH3: 1.00±0.20; VOC: 1.05±0.18) present lower values than OF_wood (CH4: 1.27±0.09; N2O: 0.021±0.006; NH3: 4.34±2.79; VOC: 0.989±0.249). A detailed composition of VOC is also presented. Terpenes were the main emitted VOC family in all the wastes studied. Higher emissions of alpha and beta pinene were found during OF_wood composting processes.

  13. Effect of carboxylic acids as compatibilizer agent on mechanical properties of thermoplastic starch and polypropylene blends.

    PubMed

    Martins, Andréa Bercini; Santana, Ruth Marlene Campomanes

    2016-01-01

    In this work, polypropylene/thermoplastic starch (PP/TPS) blends were prepared as an alternative material to use in disposable packaging, reducing the negative polymeric environmental impact. Unfortunately, this material displays morphological characteristics typical of immiscible polymer blends and a compatibilizer agent is needed. Three different carboxyl acids: myristic (C14), palmitic (C16) and stearic acids (C18) were used as natural compatibilizer agent (NCA). The effects of NCA on the mechanical, physical, thermal and morphological properties of PP/TPS blends were investigated and compared against PP/TPS with and without PP-grafted maleic anhydride (PPgMA). When compared to PP/TPS, blends with C18, PPgMA and C14 presented an improvement of 25, 22 and 17% in tensile strength at break and of 180, 194 and 259% in elongation at break, respectively. The highest increase, 54%, in the impact strength was achieved with C14 incorporation. Improvements could be seen, through scanning electron microscopy (SEM) images, in the compatibility between the immiscible components by acids incorporation. These results showed that carboxylic acids, specifically C14, could be used as compatibilizer agent and could substitute PPgMA.

  14. Antibacterial Effect and Physical-Mechanical Properties of Temporary Restorative Material Containing Antibacterial Agents.

    PubMed

    Mushashe, Amanda Mahammad; Gonzaga, Carla Castiglia; Tomazinho, Paulo Henrique; da Cunha, Leonardo Fernandes; Leonardi, Denise Piotto; Pissaia, Janes Francio; Correr, Gisele Maria

    2015-01-01

    Introduction. For the maintenance of the aseptic chain created during the treatment the coronal sealing becomes paramount. Aim. Evaluating the antibacterial effect and the physical-mechanical properties of a temporary restorative material containing different antibacterial agents. Material and Methods. Two antibacterial agents (triclosan and chloramine T) were manually added to a temporary restorative material used as base (Coltosol). The antibacterial action of the material was analyzed using the agar diffusion method, in pure cultures of Escherichia coli (ATCC BAA-2336) and Staphylococcus aureus (ATCC 11632) and mixed culture of saliva collection. The microleakage rate was analyzed using bovine teeth, previously restored with the materials, and submitted to thermocycling, in a solution of 0.5% methylene blue, for a period of 24 hours. The physical and mechanical properties of the materials analyzed were setting time, water sorption, solubility, and compression strength. Results. No marginal leakage was observed for all groups. There was no statistical significant difference in antimicrobial activity, setting time, water sorption, solubility, and compression strength among the materials. Conclusion. The addition of antibacterial agents on a temporary restorative material did not optimize the antibacterial ability of the material and also did not change its physical-mechanical properties.

  15. Effects of complexing agents on electrochemical deposition of FeS x O y thin films

    NASA Astrophysics Data System (ADS)

    Supee, Aizuddin; Ichimura, Masaya

    2016-08-01

    FeS x O y thin films were deposited on indium-tin-oxide (ITO)-coated glass substrates at 15 °C via galvanostatic electrochemical deposition from an aqueous solution containing 100 mM Na2S2O3 and 30 mM FeSO4. The effects of l(+)-tartaric acid (C4H4O6) and lactic acid [CH3CH(OH)COOH] at different concentrations were investigated. All the deposited films were amorphous. With the complexing agents, the thickness was increased, and the oxygen content was reduced significantly compared with the sample deposited without the complexing agents. In the photoelectrochemical measurement, p-type conductivity was confirmed. The photoresponsivity was not influenced significantly by the complexing agent, suggesting that the oxygen content does not drastically affect the properties of the deposited films probably because the local bonding configuration around Fe atoms in FeS x O y is similar to that in FeS2.

  16. Antibacterial Effect and Physical-Mechanical Properties of Temporary Restorative Material Containing Antibacterial Agents

    PubMed Central

    Mushashe, Amanda Mahammad; Gonzaga, Carla Castiglia; Tomazinho, Paulo Henrique; da Cunha, Leonardo Fernandes; Leonardi, Denise Piotto; Pissaia, Janes Francio; Correr, Gisele Maria

    2015-01-01

    Introduction. For the maintenance of the aseptic chain created during the treatment the coronal sealing becomes paramount. Aim. Evaluating the antibacterial effect and the physical-mechanical properties of a temporary restorative material containing different antibacterial agents. Material and Methods. Two antibacterial agents (triclosan and chloramine T) were manually added to a temporary restorative material used as base (Coltosol). The antibacterial action of the material was analyzed using the agar diffusion method, in pure cultures of Escherichia coli (ATCC BAA-2336) and Staphylococcus aureus (ATCC 11632) and mixed culture of saliva collection. The microleakage rate was analyzed using bovine teeth, previously restored with the materials, and submitted to thermocycling, in a solution of 0.5% methylene blue, for a period of 24 hours. The physical and mechanical properties of the materials analyzed were setting time, water sorption, solubility, and compression strength. Results. No marginal leakage was observed for all groups. There was no statistical significant difference in antimicrobial activity, setting time, water sorption, solubility, and compression strength among the materials. Conclusion. The addition of antibacterial agents on a temporary restorative material did not optimize the antibacterial ability of the material and also did not change its physical-mechanical properties. PMID:27347539

  17. Immunotoxicological effects of Agent Orange exposure to the Vietnam War Korean veterans.

    PubMed

    Kim, Hyoung-Ah; Kim, Eun-Mi; Park, Yeong-Chul; Yu, Ji-Yeon; Hong, Seung-Kwon; Jeon, Seong-Hoon; Park, Kui-Lea; Hur, Sook-Jin; Heo, Yong

    2003-07-01

    Immunomodulatory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) demonstrated using animals are thymic atrophy, downregulation of cytotoxic T or B lymphocyte differentiation or activation, whereas human immunotoxicities have not been investigated well. This study was undertaken to evaluate overall immunologic spectrum of the Vietnam War Korean veterans exposed to Agent Orange contaminated with TCDD. Quantity of red blood cells, hemoglobin and hematocrit in the veterans suffered from chronic diseases associated with Agent Orange exposure (Veterans-patient group) were decreased in comparison with those of the veterans without the diseases and the age-matched healthy controls, but no differences in leukocyte populations. Plasma IgG levels were lowered in the veterans than the controls, owing to significant decrease in the IgG1 levels. Increase in the IgE levels was observed in the plasma from the veterans. Alteration of T cell-mediated immunity was also resulted from activation of peripheral blood mononuclear cells with polyclonal T cell activators. Production of IFNgamma, a major cytokine mediating host resistance against infection or tumoregenesis, was lowered in the veterans-patient group. However, production of IL-4 and IL-10, representative cytokines involved with hypersensitivity induction, was enhanced in the patient group. Overall, this study suggests that military service in Vietnam and/or Agent Orange exposure disturbs immune-homeostasis resulting in dysregulation of B and T cell activities.

  18. Effect of modifying agents on the hydrophobicity and yield of zinc borate synthesized by zinc oxide

    NASA Astrophysics Data System (ADS)

    Acarali, Nil Baran; Bardakci, Melek; Tugrul, Nurcan; Derun, Emek Moroydor; Piskin, Sabriye

    2013-06-01

    The aim of this study was to synthesize zinc borate using zinc oxide, reference boric acid, and reference zinc borate (reference ZB) as the seed, and to investigate the effects of modifying agents and reaction parameters on the hydrophobicity and yield, respectively. The reaction parameters include reaction time (1-5 h), reactant ratio (H3BO3/ZnO by mass: 2-5), seed ratio (seed crystal/(H3BO3+ZnO) by mass: 0-2wt%), reaction temperature (50-120°C), cooling temperature (10-80°C), and stirring rate (400-700 r/min); the modifying agents involve propylene glycol (PG, 0-6wt%), kerosene (1wt%-6wt%), and oleic acid (OA, 1wt%-6wt%) with solvents (isopropyl alcohol (IPA), ethanol, and methanol). The results of reaction yield obtained from either magnetically or mechanically stirred systems were compared. Zinc borate produced was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and contact angle tests to identify the hydrophobicity. In conclusion, zinc borate is synthesized successfully under the optimized reaction conditions, and the different modifying agents with various solvents affect the hydrophobicity of zinc borate.

  19. Response of the forelimb vasculature to vasoactive agents: effects of ouabain.

    PubMed

    Dobbins, D E; Swindall, B T; Haddy, F J; Dabney, J M

    1985-01-01

    The effect of the local intra-arterial infusion of ouabain (11.8 micrograms/min.) on the response of the forelimb to vasoactive agents was examined. In seven dogs, bolus injections of CaCl2, MgSO4, KCl, norepinephrine, adenosine, acetylcholine, PGE1 and saline were made into the forelimb perfused at constant flow before and three times during ouabain infusion. Ouabain blocked potassium vasodilation and changed the response to CaCl2 from vasoconstriction to vasodilation. The response of the forelimb to the other vasoactive agents was initially unaffected by ouabain but with time the forelimb vasculature became less sensitive to all agents studied. These changes were not seen in a series of 5 saline infused control animals. In a third series of animals steady-state dose responses to CaCl2, Ca-gluconate and KCl were explored by infusing solutions intrabrachially at three dosages. Before ouabain, forelimb resistance increased as a function of Ca++ and decreased as a function of K+. Ouabain completely blocked potassium vasodilation and on the average blocked Ca++ vasoconstriction although a number of animals evidenced vasodilation to Ca++ during ouabain infusion. These data indicate that K+ vasodilation is Na+, K+-ATPase dependent and that Na+, K+-ATPase inhibition unmasks a vasodilatory action of locally applied Ca++.

  20. Effects of surface treatment on bond strength between dental resin agent and zirconia ceramic.

    PubMed

    Moradabadi, Ashkan; Roudsari, Sareh Esmaeily Sabet; Yekta, Bijan Eftekhari; Rahbar, Nima

    2014-01-01

    This paper presents the results of an experimental study to understand the dominant mechanism in bond strength between dental resin agent and zirconia ceramic by investigating the effects of different surface treatments. Effects of two major mechanisms of chemical and micromechanical adhesion were evaluated on bond strength of zirconia to luting agent. Specimens of yttrium-oxide-partially-stabilized zirconia blocks were fabricated. Seven groups of specimens with different surface treatment were prepared. 1) zirconia specimens after airborne particle abrasion (SZ), 2) zirconia specimens after etching (ZH), 3) zirconia specimens after airborne particle abrasion and simultaneous etching (HSZ), 4) zirconia specimens coated with a layer of a Fluorapatite-Leucite glaze (GZ), 5) GZ specimens with additional acid etching (HGZ), 6) zirconia specimens coated with a layer of salt glaze (SGZ) and 7) SGZ specimens after etching with 2% HCl (HSGZ). Composite cylinders were bonded to airborne-particle-abraded surfaces of ZirkonZahn specimens with Panavia F2 resin luting agent. Failure modes were examined under 30× magnification and the effect of surface treatments was analyzed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). SZ and HSZ groups had the highest and GZ and SGZ groups had the lowest mean shear bond strengths among all groups. Mean shear bond strengths were significantly decreased by applying a glaze layer on zirconia surfaces in GZ and SGZ groups. However, bond strengths were improved after etching process. Airborne particle abrasion resulted in higher shear bond strengths compared to etching treatment. Modes of failure varied among different groups. Finally, it is concluded that micromechanical adhesion was a more effective mechanism than chemical adhesion and airborne particle abrasion significantly increased mean shear bond strengths compared with another surface treatments.

  1. Comparison of the effects of various anticancer agents on intestinal anastomosis after intraperitoneal administration.

    PubMed

    Arikan, A Y; Senel, F M; Akman, R Y; Can, C

    1999-01-01

    In this study, the effects of intraperitoneal 5-fluorouracil (5-FU), cisplatinum (Cis), adriamycin (Adr), and methotrexate (MTX) administration on rat intestinal anastomosis were compared. Cis and MTX led to significant weight loss in the first 5 days compared with the control group. Within 14 days all rats except the MTX group nearly reached their preoperative weight. No remarkable weight loss or systemic toxicity was observed among the 5-FU and Adr groups. The anastomosis bursting pressure (ABP) at 1 week was significantly lower than that of the control group (P < 0.01 and P < 0.005, respectively). On day 14 the anastomosis bursting pressure in the Cis group was similar to that of the control group but was significantly lower in the MTX group (P < 0.002). Histopathologically, MTX avoided the development of a mucosal layer at the anastomosis site and led to ulcer formation in some of the rats. The ABPs at 7 and 14 days were similar to those in the control group. Neither of the agents had any significant mechanical or histopathologic adverse effects on anastomosis. According to the results of our study, MTX impaired the healing of the anastomosis, and we thus conclude that the intraperitoneal administration of this agent is not safe. On the other hand, Cis showed a detrimental effect on the anastomosis, particularly in the early phase, but this effect disappeared in the late phase. Cis thus should not be administered in the early postoperative phase. As a result, 5-FU and Adr were found to be the safest agents as they did not delay wound healing and did not reduce the anastomotic strength.

  2. Molecular Cloning and Characterization of Taurocyamine Kinase from Clonorchis sinensis: A Candidate Chemotherapeutic Target

    PubMed Central

    Tokuhiro, Shinji; Nagataki, Mitsuru; Jarilla, Blanca R.; Nomura, Haruka; Kim, Tae Im; Hong, Sung-Jong; Agatsuma, Takeshi

    2013-01-01

    Background Adult Clonorchis sinensis lives in the bile duct and causes endemic clonorchiasis in East Asian countries. Phosphagen kinases (PK) constitute a highly conserved family of enzymes, which play a role in ATP buffering in cells, and are potential targets for chemotherapeutic agents, since variants of PK are found only in invertebrate animals, including helminthic parasites. This work is conducted to characterize a PK from C. sinensis and to address further investigation for future drug development. Methology/Principal findings A cDNA clone encoding a putative polypeptide of 717 amino acids was retrieved from a C. sinensis transcriptome. This polypeptide was homologous to taurocyamine kinase (TK) of the invertebrate animals and consisted of two contiguous domains. C. sinensis TK (CsTK) gene was reported and found consist of 13 exons intercalated with 12 introns. This suggested an evolutionary pathway originating from an arginine kinase gene group, and distinguished annelid TK from the general CK phylogenetic group. CsTK was found not to have a homologous counterpart in sequences analysis of its mammalian hosts from public databases. Individual domains of CsTK, as well as the whole two-domain enzyme, showed enzymatic activity and specificity toward taurocyamine substrate. Of the CsTK residues, R58, I60 and Y84 of domain 1, and H60, I63 and Y87 of domain 2 were found to participate in binding taurocyamine. CsTK expression was distributed in locomotive and reproductive organs of adult C. sinensis. Developmentally, CsTK was stably expressed in both the adult and metacercariae stages. Recombinant CsTK protein was found to have low sensitivity and specificity toward C. sinensis and platyhelminth-infected human sera on ELISA. Conclusion CsTK is a promising anti-C. sinensis drug target since the enzyme is found only in the C. sinensis and has a substrate specificity for taurocyamine, which is different from its mammalian counterpart, creatine. PMID:24278491

  3. Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer

    PubMed Central

    Wang, Ping; Yoo, Byunghee; Sherman, Sarah; Mukherjee, Pinku; Ross, Alana; Pantazopoulos, Pamela; Petkova, Victoria; Farrar, Christian; Medarova, Zdravka; Moore, Anna

    2016-01-01

    The underglycosylated mucin 1 tumor antigen (uMUC1) is a biomarker that forecasts the progression of adenocarcinomas. In this study, we evaluated the utility of a dual-modality molecular imaging approach based on targeting uMUC1 for monitoring chemotherapeutic response in a transgenic murine model of pancreatic cancer (KCM triple transgenic mice). An uMUC1-specific contrast agent (MN-EPPT) was synthesized for use with magnetic resonance imaging (MRI) and fluorescence optical imaging. It consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT). KCM triple transgenic mice were given gemcitabine as chemotherapy while control animals received saline injections following the same schedule. Changes in uMUC1 levels following chemotherapy were monitored using T2-weighted MRI and optical imaging before and 24 hr after injection of the MN-EPPT. uMUC1 expression in tumors from both groups was evaluated by histology and qRT-PCR. We observed that the average delta-T2 in the gemcitabine-treated group was significantly reduced compared to the control group indicating lower accumulation of MN-EPPT, and correspondingly, a lower level of uMUC1 expression. In vivo optical imaging confirmed the MRI findings. Fluorescence microscopy of pancreatic tumor sections showed a lower level of uMUC1 expression in the gemcitabine-treated group compared to the control, which was confirmed by qRT-PCR. Our data proved that changes in uMUC1 expression after gemcitabine chemotherapy could be evaluated using MN-EPPT-enhanced in vivo MR and optical imaging. These results suggest that the uMUC1-targeted imaging approach could provide a useful tool for the predictive assessment of therapeutic response. PMID:26996122

  4. Using Physiological Measures to Assess the Effects of Animated Pedagogical Agents in Multimedia Instruction

    ERIC Educational Resources Information Center

    Romero-Hall, Enilda; Watson, Ginger; Papelis, Yiannnis

    2014-01-01

    To examine the visual attention, emotional responses, learning, perceptions and attitudes of learners interacting with an animated pedagogical agent, this study compared a multimedia learning environment with an emotionally-expressive animated pedagogical agent, with a non-expressive animated pedagogical agent, and without an agent. Visual…

  5. Effect of Ceramic Thickness and Luting Agent Shade on the Color Masking Ability of Laminate Veneers.

    PubMed

    Begum, Zubeda; Chheda, Pratik; Shruthi, C S; Sonika, Radhika

    2014-12-01

    The main objective of the study was to recognize the effect of ceramic thickness and luting agent on the extent to which the restoration masks color variations that may be present in the underlying dental structure. Two pressable ceramics were used: Lithium disilicate reinforced (IPS e.max- Ivoclar Vivadent) and Leucite reinforced (Cergo- Dentsply). Fifteen ceramic discs were manufactured from each ceramic and divided into three groups, according to the thickness (0.5, 1, 1.5 mm). To simulate the color of a dark underlying dental structure, background discs, color C3, with 20 mm diameter, were made using resin composite. The ceramic discs with varying thicknesses were seated on the dark background of the resin composite with either resinous opaque cement or resinous cement. The color parameters were determined by the CIE Lab system of colors using a spectrophotometer and color differences (ΔE) were calculated. The results were then statistically analyzed, using ANOVA test and Tukey HSD test. The ΔE values of both ceramic systems were affected by both the luting agent and the ceramic thickness (P < 0.05). The use of an opaque luting agent resulted in an increase of the ΔE* values for all ceramics tested, regardless of the thickness. For the 1.5-mm thick veneers, higher values in the color parameters were obtained for both ceramic materials. The color masking ability of ceramics used for laminate veneers is significantly affected by the thickness of the ceramic and the shade of the luting agent used.

  6. [Hypoxia and memory. Specific features of nootropic agents effects and their use].

    PubMed

    Voronina, T A

    2000-01-01

    Hypoxia and hypoxic adaptation are powerful factors of controlling memory and behavior processes. Acute hypoxia exerts a differential impact on different deficits of mnestic and cognitive functions. Instrumental reflexes of active and passive avoidance, negative learning, behavior with a change in the stereotype of learning are more greatly damaged. Memory with spatial and visual differentiation and their rearrangement change to a lesser extent and conditional reflexes are not deranged. In this contract, altitude hypoxic adaptation enhances information fixation and increases the degree and duration of retention of temporary relations. Nootropic agents with an antihypoxic action exert a marked effect on hypoxia-induced cognitive and memory disorders and the magnitude of this effect depends on the ration of proper nootropic to antihypoxic components in the spectrum of the drugs' pharmacological activity. The agents that combine a prevailing antiamnestic effect and a marked and moderate antihypoxic action (mexidole, nooglutil, pyracetam, beglymin, etc.) are most effective in eliminating different hypoxia-induced cognitive and memory disorders, nootropic drugs that have a pronounced antiamnestic activity (centrophenoxine, etc.) and no antihypoxic component also restore the main types of mnestic disorders after hypoxia, but to a lesser extent.

  7. Evaluation of protective ointments used against dermal effects of nitrogen mustard, a vesicant warfare agent.

    PubMed

    Kenar, Levent; Karayilanoğlu, Turan; Yuksel, Altan; Gunhan, Omer; Kose, Songul; Kurt, Bulent

    2005-01-01

    Mustard, a vesicant warfare agent, has cytotoxic, mutagenic, and cytostatic effects via alkylation of DNA and inhibition of DNA replication. Since symptoms appear following a latent period, it can cause some subacute and chronic effects to occur and delay in the treatment. Therefore, the main approach should be the use of protective preparation to reduce the skin toxicity. Thus, this study was conducted in guinea pigs (350-400 g) shaved in areas of 10 x 10 cm. Mechlorethamine HCl (100 mg), a nitrogen mustard derivative, in ethanol was applied by spraying on hairless regions where previously prepared pharmaceutical topical formulations were medicated before. The experimental regions of the animals were kept preserved from environmental factors. Forty-eight hours after the application of the protective ointments and mechlorethamine consecutively, skin-damaging effects were macroscopically evaluated in terms of erythema formation, ulceration, necrosis, and inflammation occurrences. Then, punch biopsy was performed from these damaged sites for histopathological evaluation. Although numerous topical formulations were prepared and tested for protection, according to microscopic examination of the pathologic sections, tissue specimen treated with the ointment containing the mixture of zinc oxide, zinc chloride, dimethylpolysiloxane in a base of petroleum jelly was determined as being the most effective protective against skin injury caused by the vesicant agent.

  8. Recent advances in biocompatible nanocarriers for delivery of chemotherapeutic cargoes towards cancer therapy.

    PubMed

    Ang, Chung Yen; Tan, Si Yu; Zhao, Yanli

    2014-07-21

    Cancer is currently one of the major diseases that has gained a lot of scientific attention. Conventional cancer therapeutics involve surgical removal of tumors from patients followed by chemotherapeutic treatment. In the use of anticancer drugs during the chemotherapy process, patients often suffer from a variety of undesirable side effects including damage to normal organs. Thus, there is an urgent need for the development of novel strategies to overcome these side effect issues. Among several strategies, the utilization of nanocarriers for anticancer drug delivery has shown improved therapeutic efficiency of the drugs with minimization of the undesirable side effects. In this review, we discuss various types of nanocarriers recently reported in the literature for application in cancer therapy. We introduce some targeting ligands that have been functionalized on nanocarriers in order to impart specificity to the nanocarriers for targeted drug delivery. We also highlight some therapeutic cargoes that are commonly used and their therapeutic mechanisms in cancer treatment. Finally, we summarize some interesting stimulus strategies for controlled release of therapeutic cargoes at tumor sites. This review is expected to inspire new ideas and create novel strategies in advancing efficient cancer therapy using nanomedicine approaches.

  9. Transgenic plants as low-cost platform for chemotherapeutic drugs screening.

    PubMed

    Vergara, Daniele; de Domenico, Stefania; Maffia, Michele; Piro, Gabriella; Di Sansebastiano, Gian-Pietro

    2015-01-20

    In this work we explored the possibility of using genetically modified Arabidopsis thaliana plants as a rapid and low-cost screening tool for evaluating human anticancer drugs action and efficacy. Here, four different inhibitors with a validated anticancer effect in humans and distinct mechanism of action were screened in the plant model for their ability to interfere with the cytoskeletal and endomembrane networks. We used plants expressing a green fluorescent protein (GFP) tagged microtubule-protein (TUA6-GFP), and three soluble GFPs differently sorted to reside in the endoplasmic reticulum (GFPKDEL) or to accumulate in the vacuole through a COPII dependent (AleuGFP) or independent (GFPChi) mechanism. Our results demonstrated that drugs tested alone or in combination differentially influenced the monitored cellular processes including cytoskeletal organization and endomembrane trafficking. In conclusion, we demonstrated that A. thaliana plants are sensitive to the action of human chemotherapeutics and can be used for preliminary screening of drugs efficacy. The cost-effective subcellular imaging in plant cell may contribute to better clarify drugs subcellular targets and their anticancer effects.

  10. Effects of oral contraceptive agents and sex steroids on carbohydrate metabolism.

    PubMed

    Kalkhoff, R K

    1972-01-01

    The article offers a general interpretation of the influence of oral contraceptive agents on glucose tolerance, emphasizing comparisons of synthetic sex hormones. Although there are conflicting reports on steroid-induced diabetes in normal women, their glucose curves are often higher when under oral contraceptive treatment, suggesting that oral contraceptives may induce a form of subclinical diabetes melitus that is reversible. Evidence from diabetic women suggests definite deliterious effects from contraceptive administration. Estradiol, estriol, and estrone may improve glucose tolerance in nondiabetic women and reduce insulin requirements in diabetics. Progesterone has little effect on carbohydrate tolerance, as did synthetic progestin. Conjugated equine estrogens (equilenine or Premarin) may provoke mild to moderate deterioration of carbohydrate tolerance. Parenterally administered natural estrogens and orally administered synthetic derivatives appear to differ sharply in their effects. Sex hormones' effects on carbohydrate metabolism likely involve interactions with insulin and endogenous glucocorticoids.

  11. New arylalkanones from Horsfieldia macrobotrys, effective antidiabetic agents concomitantly inhibiting α-glucosidase and free radicals.

    PubMed

    Ramadhan, Rico; Phuwapraisirisan, Preecha

    2015-10-15

    In search of effective antidiabetic agents having therapeutic effect by inhibiting α-glucosidase and preventive effect by scavenging free radicals, Horsfieldia macrobotrys showed promising bioactivity required for the proposed criteria. Bioassay-guided isolation of the stem bark extract resulted in two new arylalkanones named horsfieldone A (1) and maingayone D (2), together with a new flavanone C-glucoside named 8-C-β-d-glucopyranosylpinocembrin (3). Their structures and stereochemistry were determined by spectroscopic techniques as well as Mosher's method. Of isolated compounds, maingayone D (2) was the most potent inhibitors against both α-glucosidases and free radicals. The presence of additional phenolic moieties in 2 clearly indicated their critical roles in inhibitory effects. Further investigation on mechanism underlying α-glucosidase inhibition indicated that maingayone D (2) could retard the enzyme function by both competitive and noncompetitive manners.

  12. In vitro effectiveness of 13 agents in otomycosis and review of the literature.

    PubMed

    Stern, J C; Shah, M K; Lucente, F E

    1988-11-01

    Many agents have been recommended for treating otomycosis, but no preparation has been widely accepted. To compare the effectiveness of many recommended preparations, we performed an in vitro study using 15 species of fungi and yeast cultured from patients presenting with otomycosis during the past year. By measuring zones of inhibition, we assessed the effectiveness of aqueous Merthiolate, Burow's solution (2%), VoSol HC, VoSol plain, Cortisporin suspension, clotrimazole 1%, Mycostatin, amphotericin B, ethanol 95%, miconazole, tolnaftate 1%, natamycin, and flucytosine. Most otic preparations showed little or no growth inhibition. However, Merthiolate was very effective against all organisms tested, clotrimazole was very effective against most yeast and fungi tested, and nystatin had the widest spectrum of activity among the antifungals. Tolnaftate was ineffective. Vigorous cleaning of the external auditory canal remains the mainstay in treating otymycosis, but proper laboratory identification and suitable topical therapy are also important in dealing with this capricious infection.

  13. Long-term effects of the antibacterial agent triclosan on marine periphyton communities.

    PubMed

    Eriksson, K Martin; Johansson, C Henrik; Fihlman, Viktor; Grehn, Alexander; Sanli, Kemal; Andersson, Mats X; Blanck, Hans; Arrhenius, Åsa; Sircar, Triranta; Backhaus, Thomas

    2015-09-01

    Triclosan is a widely used antibacterial agent that has become a ubiquitous contaminant in freshwater, estuary, and marine environments. Concerns about potential adverse effects of triclosan have been described in several recent risk assessments. Its effects on freshwater microbial communities have been well studied, but studies addressing effects on marine microbial communities are scarce. In the present study, the authors describe short- and long-term effects of triclosan on marine periphyton (microbial biofilm) communities. Short-term effects on photosynthesis were estimated after 60 min to 210 min of exposure. Long-term effects on photosynthesis, chlorophyll a fluorescence, pigment content, community tolerance, and bacterial carbon utilization were studied after exposing periphyton for 17 d in flow-through microcosms to 0.316 nM to 10,000 nM triclosan. Results from the short-term studies show that triclosan is toxic to periphyton photosynthesis. Half maximal effective concentration (EC50) values of 1080 nM and 3000 nM were estimated using (14)CO2-incorporation and pulse amplitude modulation (PAM) fluorescence measurements, respectively. After long-term triclosan exposure in flow-through microcosms, photosynthesis estimated using PAM fluorometry was not inhibited by triclosan concentrations up to 1000 nM but instead increased with increasing triclosan concentration. Similarly, at exposure concentrations of 31.6 nM and higher, triclosan caused an increase in photosynthetic pigments. At 316 nM triclosan, the pigment amounts were increased by a factor of 1.4 to 1.9 compared with the control level. Pollution-induced community tolerance was observed for algae and cyanobacteria at 100 nM triclosan and higher. Despite the widespread use of triclosan as an antibacterial agent, the compound did not have any effects on bacterial carbon utilization after long-term exposure.

  14. [The effect of 2 bleaching agents on the enamel surface. An in-vitro study].

    PubMed

    Llena Puy, M C; Forner Navarro, L; Ferrandez, A; Faus Llacer, J V

    1992-01-01

    We present a study "in vitro" of the effect of bleaching agents on dental surfaces using the "Walking bleaching technique". We found that hydrogen peroxide bleached more quickly than carbamide although, after a period of six weeks, the results were the same as far as whitening was concerned. In the scanning electron microscope we observed significantly different changes in each case. Carbamide caused a regular and uniform opening of the enamel prisms of the surface while hydrogen peroxide produced more severe superficial destruction with the appearance of patterning similar to the acid etching, and the presence of some crystalline areas emerging from the body of the prisms.

  15. Effect of a silane coupling agent on the mechanical properties of a microfibrillated cellulose composite.

    PubMed

    Ifuku, Shinsuke; Yano, Hiroyuki

    2015-03-01

    Composite materials reinforced with microfibrillated cellulose (MFC) fibers were prepared and characterized in terms of their mechanical properties. The surface of the MFC fibers was treated with a silane coupling reagent having an NH2 functional group to improve fiber-matrix adhesion. Due to the unique structure of the MFC, which consists of nano-order-scale interconnected fibrils and microfibrils with greatly expanded surface area and submicron pore size compared to conventional cellulose, it was possible to enhance the effect of silane coupling agent and thereby improve the compatibility between the fibers and matrix and also the dispersibility of fibers. The Young's modulus was significantly increased to more than 70%.

  16. Effect of selective sorptive agents on leachability of {sup 137}Cs and {sup 90}Sr

    SciTech Connect

    Spence, R.D.

    1998-06-01

    Decades ago it was established that illite effectively improves {sup 137}Cs leach resistance. Subsequently, illite has become a standard ingredient used at Oak Ridge National Laboratory in grouts developed to stabilize {sup 137}Cs. Adding illite improves {sup 137}Cs leach resistance by three orders of magnitude, and increasing the illite concentration can add another order of magnitude improvement. Adding crystalline silicotitanate, a selective sorptive agent developed more recently for {sup 137}Cs, not only improves {sup 137}Cs leach resistance by an order-of-magnitude over that obtained using illite but also improves {sup 85}Sr leach resistance by two orders of magnitude.

  17. The effect of iron on the biodistribution of bone scanning agents in humans

    SciTech Connect

    Choy, D.; Murray, I.P.; Hoschl, R.

    1981-07-01

    Nine patients with chronic iron overload, resulting from either repeated transfusions or hemochromatosis, had bone scans that were characterized by a reduction of bony uptake, marked increase in renal activity, and a significant increase in soft-tissue accumulation of 99mTc-labeled bone-seeking agents. These findings were supported by semiquantitative computer analysis. The probable mechanisms of altered biodistribution and the possible role of serum ferritin are discussed. The importance of realizing the effect of excess iron on skeletal scintigraphy is further emphasized by the results of bone scanning in another patient in whom acute iron overload following infusion of iron-dextran resulted in excessive blood pool labeling.

  18. The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems

    PubMed Central

    Wu, Min; Frieboes, Hermann B.; Chaplain, Mark A.J.; McDougall, Steven R.; Cristini, Vittorio; Lowengrub, John

    2014-01-01

    Vascularized tumor growth is characterized by both abnormal interstitial fluid flow and the associated interstitial fluid pressure (IFP). Here, we study the effect that these conditions have on the transport of therapeutic agents during chemotherapy. We apply our recently developed vascular tumor growth model which couples a continuous growth component with a discrete angiogenesis model to show that hypertensive IFP is a physical barrier that may hinder vascular extravasation of agents through transvascular fluid flux convection, which drives the agents away from the tumor. This result is consistent with previous work using simpler models without blood flow or lymphatic drainage. We consider the vascular/interstitial/lymphatic fluid dynamics to show that tumors with larger lymphatic resistance increase the agent concentration more rapidly while also experiencing faster washout. In contrast, tumors with smaller lymphatic resistance accumulate less agents but are able to retain them for a longer time. The agent availability (area-under-the curve, or AUC) increases for less permeable agents as lymphatic resistance increases, and correspondingly decreases for more permeable agents. We also investigate the effect of vascular pathologies on agent transport. We show that elevated vascular hydraulic conductivity contributes to the highest AUC when the agent is less permeable, but leads to lower AUC when the agent is more permeable. We find that elevated interstitial hydraulic conductivity contributes to low AUC in general regardless of the transvascular agent transport capability. We also couple the agent transport with the tumor dynamics to simulate chemotherapy with the same vascularized tumor under different vascular pathologies. We show that tumors with an elevated interstitial hydraulic conductivity alone require the strongest dosage to shrink. We further show that tumors with elevated vascular hydraulic conductivity are more hypoxic during therapy and that the

  19. Sunscreening Agents

    PubMed Central

    Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; Naveen Kumar, B.R.

    2013-01-01

    The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food and Drug Administration and European Union have incorporated changes in their guidelines to help consumers select products based on their sun protection factor and protection against ultraviolet radiation, whereas the Indian regulatory agency has not yet issued any special guidance on sunscreening agents, as they are classified under cosmetics. In this article, the authors discuss the pharmacological actions of sunscreening agents as well as the available formulations, their benefits, possible health hazards, safety, challenges, and proper application technique. New technologies and scope for the development of sunscreening agents are also discussed as well as the role of the physician in patient education about the use of these agents. PMID:23320122

  20. Antiparkinson drugs used as prophylactics for nerve agents: studies of cognitive side effects in rats.

    PubMed

    Myhrer, Trond; Enger, Siri; Aas, Pål

    2008-06-01

    Antiparkinson agents possess excellent anticonvulsant properties against nerve agent-induced seizures by exerting both cholinergic and glutamatergic antagonisms. It is important, however, that drugs used as prophylactics not by themselves cause impairment of cognitive capability. The purpose of the present study was to make a comparative assessment of potential cognitive effects of benactyzine (0.3 mg/kg), biperiden (0.11 mg/kg), caramiphen (10 mg/kg), procyclidine (3 mg/kg), and trihexyphenidyl (0.12 mg/kg) separately and each in combination with physostigmine (0.1 mg/kg). The results showed that benactyzine, caramiphen, and trihexyphenidyl reduced rats' innate preference for novelty, whereas biperiden and procyclidine did not. When benactyzine, caramiphen, and trihexyphenidyl were combined with physostigmine the cognitive impairment disappeared. This counteracting effect, however, caused changes in locomotor and rearing activities not seen by each drug alone. Acetylcholinesterase inhibitors and anticholinergics used as prophylactics can offset each other, but exceptions are observed in a previous study when a very potent anticholinergic (scopolamine) or a high dose of procyclidine still results in cognitive deficits in spite of coadministration with physostigmine. Among the present drugs tested, procyclidine appears to be a robust anticonvulsant with few cognitive side effects.

  1. The effect of carbamide peroxide bleaching agents on the microhardness of dental ceramics.

    PubMed

    Passos, Sheila P; Vanderlei, Aleska D; Salazar-Marocho, Susana M; Azevedo, Sarina M B; Vasquez, Vanessa Z C; Kimpara, Estevão T

    2010-01-01

    This study examined the effect of 10% and 16% carbamide peroxide bleaching agents on the surface microhardness of micro-particulate feldspathic ceramics (VM7 and VM13, Vita Zahnfabrik). Forty specimens (8-mm diameter, 2-mm thickness) were divided into four groups (n=10): GI-VM7 + 10% Whiteness, G2-VM7 + 16% Whiteness, G3-VM13 + 10% and G4-VM13 + 16% Whiteness. The home-use bleaching agents were applied for 8 hours on 15 days, and the specimens were stored in distilled water at 37 degrees C. The Vickers hardness number (HV) was determined for each specimen. Data were analyzed by the Wilcoxon and Mann-Whitney tests (p < 0.05). The microhardness values before exposure were: g1-433 (57); g2-486 (22); g3-509 (28); g4-518 (24), and after exposure: G1-349 (32); G2-496 (95); G3-519 (38); G4-502 (81). G2 exhibited a higher and significant difference than GI in VM7 groups, and the effect of bleaching concentration was shown to be significant by the Mann-Whitney test. And for VM13, both the Wilcoxon and Mann-Whitney tests showed no significant differences. When using 10% carbamide peroxide, the microhardness of VM7 ceramic was affected, and there were no effect on the microhardness between VM7 and VM13 ceramics when 16% carbamide peroxide was used.

  2. Effect of anti-glycolytic agents on tumour cells in vitro

    NASA Astrophysics Data System (ADS)

    Korshunov, D. A.; Kondakova, I. V.

    2016-08-01

    A metabolic change is one of the tumour hallmarks, which has recently attracted a great amount of attention. One of the main metabolic characteristics of tumour cells is a high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in a glycolysis pathway than that in a tricarboxylic acid cycle. The Warburg effect constitutes a fundamental adaptation of tumour cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumour glycolysis may become an attractive target for cancer therapy. Here, we research the effect of potential anticancer agents on tumour cells in vitro. In our study, we found a high sensitivity of tumour cells to anti-glycolityc drugs. In addition, tumour cells are more resistant to the agents studied in comparison with normal cells. We also observed an atypical cooperative interaction of tumour cells in the median lethal dose of drugs. They formed the specific morphological structure of the surviving cells. This behavior is not natural for the culture of tumour cells. Perhaps this is one of the mechanisms of cells' adaptation to the aggressive environment.

  3. Effects of raw materials and bulking agents on the thermophilic composting process.

    PubMed

    Tang, Jing-Chun; Zhou, Qixing; Katayama, Arata

    2010-05-01

    Three typical biological solid wastes, animal manure, garbage, and sewage sludge, were compared with regard for the composting process and the changes in microbial community structure. The effect of different bulking agents such as rice straw, vermiculite, sawdust, and waste paper were compared in manure compost. The differences in the microbial community were characterized by the quinone profile method. The highest mass reduction was found in garbage composting (56.8%), compared to manure and sludge at 25% and 20.2%, respectively. A quinone content of 305.2 micromol/kg was observed in the late stage of garbage composting, although the diversity index of quinone profile was 9.7, lower than that in manure composting. The predominant quinone species were found to be MK-7, which corresponds to gram positive bacteria with low G+C content such as Bacillus. The predominance of MK-7 was especially found in garbage and sludge composting process, while the increase in quinones with partially saturated long side chain was shown in late composting process of manure, which corresponded to the proliferation of Actinobacteria. The effect of different bulking agents on the composting process was much smaller than the effect of different raw materials. High organic matter content in the raw materials results in a higher microbial biomass and activity, which was connected to the high mass reduction rate.

  4. Potential water-quality effects from iron cyanide anticaking agents in road salt

    SciTech Connect

    Paschka, M.G.; Ghosh, R.S.; Dzombak, D.A.

    1999-10-01

    Water-soluble iron cyanide compounds are widely used as anticaking agents in road salt, which creates potential contamination of surface and groundwater with these compounds when the salt dissolves and is washed off roads in runoff. This paper presents a summary of available information on iron cyanide use in road salt and its potential effects on water quality. Also, estimates of total cyanide concentrations in snow-melt runoff from roadways are presented as simple mass-balance calculations. Although available information does not indicate a widespread problem, it also is clear that the water-quality effects of cyanide in road salt have not been examined much. Considering the large, and increasing, volume of road salt used for deicing, studies are needed to determine levels of total and free cyanide in surface and groundwater adjacent to salt storage facilities and along roads with open drainage ditches. Results could be combined with current knowledge of the fate and transport of cyanide to assess water-quality effects of iron cyanide anticaking agents used in road salt.

  5. Effect of a novel chelating agent on defect removal during post-CMP cleaning

    NASA Astrophysics Data System (ADS)

    Hong, Jiao; Niu, Xinhuan; Liu, Yuling; He, Yangang; Zhang, Baoguo; Wang, Juan; Han, Liying; Yan, Chenqi; Zhang, Jin

    2016-08-01

    Chemical mechanical polishing (CMP) has become widely accepted for the planarization of device interconnect structures in deep submicron semiconductor manufacturing. However, during CMP process the foreign particles, metal contaminants, and other chemical components are introduced onto the wafer surface, so CMP process is considered as one of the dirtiest process to wafer surface defects which may damage the GLSI patterns and the metallic impurities can induce many crystal defects in wafers during the following furnace processing. Therefore, the post-CMP cleaning of wafers has become a key step in successful CMP process and the polyvinyl alcohol (PVA) brush cleaning is the most effective method for post-CMP in situ cleaning. In this study, the effect of the chelating agent with different concentrations on defect removal by using PVA brush cleaning was discussed emphatically. It can be seen from the surface images obtained by scanning electron microscopy and KLA digital comparison system analysis confirmed that the chelating agent can effectively act on the defect removal.

  6. Absence of beneficial effects on rabbit sperm cell cryopreservation by several antioxidant agents.

    PubMed

    Maya-Soriano, M J; Taberner, E; Sabés-Alsina, M; Piles, M; Lopez-Bejar, M

    2015-02-01

    The generation of reactive oxygen species associated with cryopreservation could be responsible for mammalian sperm damage and the limitable value of stored semen in artificial insemination. The aim of this study was to assess several antioxidant agents supplemented in a commercial freezing extender (Gent B®) in order to improve post-thaw rabbit sperm quality. Ejaculates of 26 New Zealand White rabbit bucks were collected, evaluated and frozen using a conventional protocol. Antioxidant agents were tested at different concentrations: bovine serum albumin (BSA; 5, 30 or 60 mg/ml), retinol (RO; 50, 100 or 200 μM) and retinyl (RI; 0.282 or 2.82 μg/ml). Per cent viability, morphological abnormalities and intact acrosomes were determined using eosin-nigrosin staining. Motility and progressivity were analyzed by computer-assisted sperm analysis (CASA). In general, all sperm quality parameters were negatively affected by the cryopreservation process, the largest effect seen was for total motility. The addition of antioxidant agents did not improve thaw sperm quality. Furthermore, for RI groups a significant decrease in sperm quality parameters was recorded. In conclusion, rabbit sperm quality is negatively affected by the cryopreservation process. To our knowledge this report is the first using these antioxidants to supplement rabbit freezing extender. BSA and RO at concentrations used in the study did not improve sperm quality parameters after thawing, whereas RI supplementation appeared to be toxic. More studies are required to find the appropriate antioxidants necessary and their most effective concentrations to improve rabbit post-thaw sperm quality.

  7. Effectiveness of dental bleaching in depth after using different bleaching agents

    PubMed Central

    Lima, Débora A N L.; Aguiar, Flávio H B.; Bertoldo, Carlos E S.; Ambrosano, Gláucia M B.; Lovadino, José R.

    2013-01-01

    Objectives: This study evaluated the effectiveness of low- and high-concentration bleaching agents on enamel and deep dentin. Study design: Stained bovine incisors fragments were randomized placed into 10 groups (n=5), according to the sample thicknesses (2.0 mm or 3.5 mm) and bleaching agent: 10% carbamide peroxide (CP) (4 h a day/21 days); 6% hydrogen peroxide (HP) with calcium (1:30 h a day/21 days); HP 20% with calcium (50 min a day/3 sessions with a 7-day interval); HP 35% (3 x 15 min a day/3 sessions with a 7-day interval); HP 35% with calcium (40 min a day/3 sessions with a 7-day interval). The samples were stored in artificial saliva during the experiment. The color change was evaluated using a spectrophotometer at the initial analysis, after artificially staining with black tea and after each of the bleaching weeks, and data was expressed in CIE Lab System values. The L* coordinate data was submitted to analysis of variance and Tukey-Kramer test and the ?E values data was submitted for analysis of variance in a split-plot ANOVA and Tukey’s test (?=0.05). Results: None of the bleaching agents tested differed from the reflectance values on the enamel surface. For deep dentin HP 20% and HP 35%, both with calcium, showed the lowest reflectance values, which differed from CP 10%. Conclusion: It is concluded that high concentration hydrogen peroxide with calcium was less effective in deep dentin than 10% carbamide peroxide. Key words:Dental bleaching; hydrogen peroxide; carbamide peroxide; dental staining. PMID:24455056

  8. Effect of antibacterial agents on the surface hardness of a conventional glass-ionomer cement

    PubMed Central

    TÜZÜNER, Tamer; ULUSU, Tezer

    2012-01-01

    In atraumatic restorative treatment (ART), caries removal with hand excavation instruments is not as efficient as that with rotary burs in eliminating bacteria under the glass ionomer cements (GICs). Thus, different antibacterial agents have been used in recent studies to enhance the antibacterial properties of the GICs, without jeopardizing their basic physical properties. Objective The objective of this study was to evaluate the effect of antibacterial agents on the surface hardness of a conventional GIC (Fuji IX) using Vickers microhardness [Vickers hardness number (VHN)] test. Material and Methods Cetrimide (CT), cetylpyridinium chloride (CPC) and chlorhexidine (CHX) were added to the powder and benzalkonium chloride (BC) was added to the liquid of Fuji IX in concentrations of 1% and 2%, and served as the experimental groups. A control group containing no additive was also prepared. After the completion of setting reaction, VHN measurements were recorded at 1, 7, 15, 30, 60, and 90 days after storage in 37ºC distilled water. A one-way ANOVA was performed followed by a Dunnett t test and Tamhane T2 tests and also repeated measurements ANOVA was used for multiple comparisons in 95% confidence interval. Results VHN results showed significant differences between the control and the experimental groups at all time periods (p<0.05 for all). Significant differences were observed between all study periods for individual groups (p<0.05). After 7 days, VHNs were decreased in all experimental groups while they continued to increase in the control group. BC and CHX groups demonstrated the least whereas CT and CPC groups exhibited most adverse effect on the hardness of set cements. Conclusions Despite the decreased microhardness values in all experimental groups compared to the controls after 7 up to 90 days, incorporating certain antibacterial agents into Fuji IX GIC showed tolerable microhardness alterations within the limitations of this in vitro study. PMID:22437677

  9. Thickening agents used for dysphagia management: effect on bioavailability of water, medication and feelings of satiety

    PubMed Central

    2013-01-01

    Dysphagia is the medical term for difficulty swallowing. Thickened liquids are often used in the management of dysphagia to improve bolus control and to help prevent aspiration. A range of starches and gums has historically been used to thicken liquids. Although thickened liquids improve swallow safety, they appear to have a great potential for unintended physiological consequences. Initial concerns were raised about the impact of thickeners on water binding due to the high prevalence of dehydration amongst individuals with dysphagia. Thankfully, regardless of thickening agent, thickeners do not affect water bioavailability. This effect holds true even for extremely thick fluids. However, bioavailability of medication is impaired with viscous substances. Liquids thickened to as little as 150 mPa.s retards drug release. In addition, feelings of satiety and thirst increase with increasingly viscous fluids. Flavour deteriorates with increasing thickness regardless of thickening agent. Therapeutically clinicians often prescribe small volumes of thickened liquids, consumed often. Yet small volumes of thick substances consumed with a long oral processing time, which is common for individuals with dysphagia, reduces the amount consumed. A combination of poor flavour, and increasing feelings of fullness result in little motivation and poor physiologic drive to consume thickened liquids. This review provides evidence from the dysphagia, pharmaceutical and food technology literature to show unintended side effects of thickened liquids that contribute to dehydration and potential sub-theraputic medication levels for individuals with dysphagia. The physical property of viscosity rather than a particular thickening agent appears to be key. Provision of “spoon-thick” or “extremely thick liquids” is particularly likely to contribute to dehydration and poor bioavailability of solid dose medication. Clinicians are encouraged to prescribe the minimal level of thickness

  10. Comparison of the lethal effects of chemical warfare nerve agents across multiple ages.

    PubMed

    Wright, Linnzi K M; Lee, Robyn B; Vincelli, Nicole M; Whalley, Christopher E; Lumley, Lucille A

    2016-01-22

    Children may be inherently more vulnerable than adults to the lethal effects associated with chemical warfare nerve agent (CWNA) exposure because of their closer proximity to the ground, smaller body mass, higher respiratory rate, increased skin permeability and immature metabolic systems. Unfortunately, there have only been a handful of studies on the effects of CWNA in pediatric animal models, and more research is needed to confirm this hypothesis. Using a stagewise, adaptive dose design, we estimated the 24h median lethal dose for subcutaneous exposure to seven CWNA in both male and female Sprague-Dawley rats at six different developmental times. Perinatal (postnatal day [PND] 7, 14 and 21) and adult (PND 70) rats were more susceptible than pubertal (PND 28 and 42) rats to the lethal effects associated with exposure to tabun, sarin, soman and cyclosarin. Age-related differences in susceptibility were not observed in rats exposed to VM, Russian VX or VX.

  11. Showering effectiveness for human hair decontamination of the nerve agent VX.

    PubMed

    Josse, Denis; Wartelle, Julien; Cruz, Catherine

    2015-05-05

    In this work, our goals were to establish whether hair decontamination by showering one hour post-exposure to the highly toxic organophosphate nerve agent VX was effective, whether it required the addition of a detergent to water and, if it could be improved by using the adsorbent Fuller's Earth (FE) or the Reactive Skin Decontamination Lotion (RSDL) 30 min prior to showering. Hair exposure to VX and decontamination was performed by using an in vitro model. Hair showering led to 72% reduction of contamination. Addition of detergent to water slightly increased the decontamination effectiveness. Hair treatment with FE or RSDL improved the decontamination rate. Combination of FE use and showering, which yielded a decontamination factor of 41, was demonstrated to be the most effective hair decontamination procedure. Hair wiping after showering was shown to contribute to hair decontamination. Altogether, our results highlighted the importance of considering hair decontamination as an important part of body surface decontamination protocols.

  12. Phase II trial of pegylated liposomal doxorubicin (Caelyx) plus Gemcitabine in chemotherapeutically pretreated patients with advanced breast cancer.

    PubMed

    Ulrich-Pur, Herbert; Kornek, Gabriela V; Haider, Karin; Kwasny, Werner; Payrits, Thomas; Dworan, Nina; Vormittag, Laurenz; Depisch, Dieter; Lang, Fritz; Scheithauer, Werner

    2007-01-01

    A phase II trial was performed to investigate the efficacy and tolerance of combined gemcitabine and liposomal doxorubicin +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapeutically pretreated metastatic breast cancer. Thirty-four patients were entered in this trial. Chemotherapy consisted of gemcitabine and liposomal doxorubicin +/- G-CSF. Twenty seven patients received this regimen as 2nd line therapy, five patients as 3rd line and two patients as 4th line therapy after having failed taxane- and/or anthracycline-based chemotherapy or other drug combinations. After a median of six courses, an overall response rate of 26% (9 PR in 34 enrolled patients) was observed; 14 patients had disease stabilization (41%), and eight (24%) progressed. Three patients were not evaluable for response due to anaphylaxis after the first course and protracted thrombocytopenia. The median TTP was 7.5 months, and median overall survival was 15 months. Myelosuppression was the most frequently observed toxicity. Non-haematological side effects were generally mild to moderate. Our data suggest that gemcitabine and liposomal doxorubicin +/- G-CSF is an effective and fairly well tolerated regimen for chemotherapeutically pretreated patients with advanced breast cancer.

  13. Effect of cleaning dentine with soap and pumice on shear bond strength of dentine-bonding agents.

    PubMed

    Bachmann, M; Paul, S J; Lüthy, H; Schärer, P

    1997-06-01

    This in vitro study reports on the cleaning effect of different soaps on the shear bond strength of various dentine-bonding agents. Human teeth were coated with provisional cements for 24 h or for 14 days. After removing the provisional cements with a scaler, the dentinal surface was cleaned with a cotton pellet and non-fluoridated flour of pumice and soap for 10 sec. Different dentine-bonding agents and a luting resin were bonded to the dentinal surface according to manufacturers' instructions with the bonding agent and the composite material being light-cured at the same time. The bonding agents were tested under intrapulpal pressure and with thermal cycling to imitate physiological conditions. Compared with cleaning the dentine with water and pumice, all soaps investigated in this study decreased the shear bond strength values of the tested dentine-bonding agents considerably.

  14. [Effect of olopatadine hydrochloride, a novel antiallergic agent, on the QT interval in dogs].

    PubMed

    Iwamoto, K; Ikeda, J; Nito, M; Kosaka, N; Ichikawa, S; Kobayashi, H; Ohmori, K

    2001-06-01

    Olopatadine hydrochloride (olopatadine), a novel antiallergic agent, is effective in the treatment of allergic rhinitis, chronic urticaria, eczema and dermatitis. It has been reported that terfenadine and astemizole cause side effects on the circulatory system such as QT prolongation followed by serious ventricular arrhythmias (torsades de pointes). To investigate the possibility of QT prolongation, we used both conscious normal dogs and hypokalemia-anesthetized dogs under two conditions: 1) olopatadine used alone and 2) olopatadine used in combination with itraconazole, the CYP3A4-inhibiting antifungal agent, in the present investigation. The group treated with terfenadine alone (30 mg/kg, p.o.) and the group treated with a combination of terfenadine (10 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) had a significantly prolonged QT interval. On the other hand, the group treated with olopatadine alone (30 mg/kg, p.o.) and the group treated with a combination of olopatadine (30 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) did not show any significant changes in QT interval. Moreover, olopatadine (1 and 5 mg/kg, i.v.) did not influence the QT interval in hypokalemia-anesthetized dogs. These results suggest that there is very little possibility of QT prolongation as a result of clinically used olopatadine.

  15. Highly magnetic iron carbide nanoparticles as effective T2 contrast agents

    NASA Astrophysics Data System (ADS)

    Huang, Guoming; Hu, Juan; Zhang, Hui; Zhou, Zijian; Chi, Xiaoqin; Gao, Jinhao

    2013-12-01

    This paper reports that iron carbide nanoparticles with high air-stability and strong saturation magnetization can serve as effective T2 contrast agents for magnetic resonance imaging. Fe5C2 nanoparticles (~20 nm in diameter) exhibit strong contrast enhancement with an r2 value of 283.2 mM-1 S-1, which is about twice as high as that of spherical Fe3O4 nanoparticles (~140.9 mM-1 S-1). In vivo experiments demonstrate that Fe5C2 nanoparticles are able to produce much more significant MRI contrast enhancement than conventional Fe3O4 nanoparticles in living subjects, which holds great promise in biomedical applications.This paper reports that iron carbide nanoparticles with high air-stability and strong saturation magnetization can serve as effective T2 contrast agents for magnetic resonance imaging. Fe5C2 nanoparticles (~20 nm in diameter) exhibit strong contrast enhancement with an r2 value of 283.2 mM-1 S-1, which is about twice as high as that of spherical Fe3O4 nanoparticles (~140.9 mM-1 S-1). In vivo experiments demonstrate that Fe5C2 nanoparticles are able to produce much more significant MRI contrast enhancement than conventional Fe3O4 nanoparticles in living subjects, which holds great promise in biomedical applications. Electronic supplementary information (ESI) available: Supplementary figures and experimental details. See DOI: 10.1039/c3nr04691e

  16. Effect of tooth bleaching agents on protein content and mechanical properties of dental enamel.

    PubMed

    Elfallah, Hunida M; Bertassoni, Luiz E; Charadram, Nattida; Rathsam, Catherine; Swain, Michael V

    2015-07-01

    This study investigated the effect of two bleaching agents, 16% carbamide peroxide (CP) and 35% hydrogen peroxide (HP), on the mechanical properties and protein content of human enamel from freshly extracted teeth. The protein components of control and treated enamel were extracted and examined on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Marked reduction of the protein matrix and random fragmentation of the enamel proteins after bleaching treatments was found. The mechanical properties were analyzed with Vickers indentations to characterize fracture toughness, and nanoindentation to establish enamel hardness, elastic modulus and creep deformation. Results indicate that the hardness and elastic modulus of enamel were significantly reduced after treatment with CP and HP. After bleaching, the creep deformation at maximum load increased and the recovery upon unloading reduced. Crack lengths of CP and HP treated enamel were increased, while fracture toughness decreased. Additionally, the microstructures of fractured and indented samples were examined with field emission gun scanning electron microscopy (FEG-SEM) showing distinct differences in the fracture surface morphology between pre- and post-bleached enamel. In conclusion, tooth bleaching agents can produce detrimental effects on the mechanical properties of enamel, possibly as a consequence of damaging or denaturing of its protein components.

  17. A useful way to develop effective in vivo skin optical clearing agents.

    PubMed

    Shi, Rui; Guo, Li; Zhang, Chao; Feng, Wei; Li, Peng; Ding, Zhihua; Zhu, Dan

    2016-12-23

    Skin optical clearing has shown tremendous potential in improving various optical imaging performances, but there is some certain blindness in screening out high-efficiency in vivo optical clearing methods. In this work, three optical clearing agents: sucrose (Suc), fructose (Fruc) and PEG-400 (PEG), and two chemical penetration enhancers: propylene glycol (PG) and thiazone (Thiaz) were used. PEG was firstly mixed with the two penetration enhancers, respectively, and then mixed with Fruc and Suc, respectively, to obtain six kinds of skin optical clearing agents (SOCAs). Optical coherence tomography angiography was applied to monitor SOCAs-induced changes in imaging performances, skin optical properties, refractive index mismatching extent, and permeability rate. Experimental results demonstrated that PEG+Thiaz+Suc has the optimal capacity in enhancing the imaging performances, decreasing the scattering and the refractive index mismatching since Thiaz is superior to PG, and Suc is superior to Fruc. This study indicates that the optimal SOCA can be obtained directly by means of additionally adding or replacing the similar category substance in preexisting SOCAs with some more effective reagents. It not only provides an optimal SOCA, but also provides a useful way to develop more effective SOCAs. Cross-section skin structural texture (a), reconstructed blood flow distribution information (b), before or after treated with different SOCAs.

  18. HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function

    PubMed Central

    Garrido, Carolina; Spivak, Adam M.; Soriano-Sarabia, Natalia; Checkley, Mary Ann; Barker, Edward; Karn, Jonathan; Planelles, Vicente; Margolis, David M.

    2016-01-01

    In an effort to clear persistent HIV infection and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is, therefore, critical to understand the impact of latency-reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors [SAHA or vorinostat (VOR), romidepsin, and panobinostat (PNB)] and two protein kinase C agonists [prostratin (PROST) and ingenol] on the antiviral activity, cytotoxicity, cytokine secretion, phenotype, and viability of primary NK cells. We found that ex vivo exposure to VOR had minimal impact on all parameters assessed, while PNB caused a decrease in NK cell viability, antiviral activity, and cytotoxicity. PROST caused non-specific NK cell activation and, interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection. PMID:27708642

  19. Highly effective bacterial agents against Cimbex quadrimaculatus (Hymenoptera: Cimbicidae): isolation of bacteria and their insecticidal activities.

    PubMed

    Cakici, Filiz Ozkan; Ozgen, İnanc; Bolu, Halil; Erbas, Zeynep; Demirbağ, Zihni; Demir, İsmail

    2015-01-01

    Cimbex quadrimaculatus (Hymenoptera: Cimbicidae) is one of the serious pests of almonds in Turkey and worldwide. Since there is no effective control application against this pest, it has been a serious problem up to now. Therefore, we aimed to find an effective bacterium that can be utilized as a biocontrol agent against C. quadrimaculatus in pest management. We isolated seven bacteria from dead and live C. quadrimaculatus larvae, and evaluated the larvicidal potency of all isolates on the respective pest. Based on the morphological, physiological, biochemical and molecular properties (partial sequence of 16S rRNA gene), the isolates were identified to be Bacillus safensis (CQ1), Bacillus subtilis (CQ2), Bacillus tequilensis (CQ3), Enterobacter sp. (CQ4), Kurthia gibsonii (CQ5), Staphylococcus sp. (CQ6) and Staphylococcus sciuri (CQ7). The results of the larvicidal activities of these isolates indicated that the mortality value obtained from all treatments changed from 58 to 100 %, and reached 100 % with B. safensis (CQ1) and B. subtilis (CQ2) on the 3rd instar larvae within 10 days of application of 1.89 × 10(9) cfu/mL bacterial concentration at 25 °C under laboratory conditions. Findings from this study indicate that these isolates appear to be a promising biocontrol agent for C. quadrimaculatus.

  20. HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function.

    PubMed

    Garrido, Carolina; Spivak, Adam M; Soriano-Sarabia, Natalia; Checkley, Mary Ann; Barker, Edward; Karn, Jonathan; Planelles, Vicente; Margolis, David M

    2016-01-01

    In an effort to clear persistent HIV infection and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is, therefore, critical to understand the impact of latency-reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors [SAHA or vorinostat (VOR), romidepsin, and panobinostat (PNB)] and two protein kinase C agonists [prostratin (PROST) and ingenol] on the antiviral activity, cytotoxicity, cytokine secretion, phenotype, and viability of primary NK cells. We found that ex vivo exposure to VOR had minimal impact on all parameters assessed, while PNB caused a decrease in NK cell viability, antiviral activity, and cytotoxicity. PROST caused non-specific NK cell activation and, interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection.

  1. The effects of node exclusion on the centrality measures in graph models of interacting economic agents

    NASA Astrophysics Data System (ADS)

    Caetano, Marco Antonio Leonel; Yoneyama, Takashi

    2015-07-01

    This work concerns the study of the effects felt by a network as a whole when a specific node is perturbed. Many real world systems can be described by network models in which the interactions of the various agents can be represented as an edge of a graph. With a graph model in hand, it is possible to evaluate the effect of deleting some of its edges on the architecture and values of nodes of the network. Eventually a node may end up isolated from the rest of the network and an interesting problem is to have a quantitative measure of the impact of such an event. For instance, in the field of finance, the network models are very popular and the proposed methodology allows to carry out "what if" tests in terms of weakening the links between the economic agents, represented as nodes. The two main concepts employed in the proposed methodology are (i) the vibrational IC-Information Centrality, which can provide a measure of the relative importance of a particular node in a network and (ii) autocatalytic networks that can indicate the evolutionary trends of the network. Although these concepts were originally proposed in the context of other fields of knowledge, they were also found to be useful in analyzing financial networks. In order to illustrate the applicability of the proposed methodology, a case of study using the actual data comprising stock market indices of 12 countries is presented.

  2. The Effects of Peer-Like and Expert-Like Pedagogical Agents on Learners' Agent Perceptions, Task-Related Attitudes, and Learning Achievement

    ERIC Educational Resources Information Center

    Liew, Tze Wei; Tan, Su-Mae; Jayothisa, Chandrika

    2013-01-01

    The present study examined the impact of peer-like and expert-like agent stereotypes, as operationalized by agent's image and voice, on learners' agent perceptions, task-related attitudes, and learning achievement. 56 university freshmen (23 males and 33 females) interacted with either the peer-like agent (female college student) or the…

  3. Effects of the methyltrimethoxysilane coupling agent on phenolic and miscanthus composites containing calcium sulfite scrubber material

    NASA Astrophysics Data System (ADS)

    Jones, Sean

    The purpose of this research is to test the effects of methyltrimethoxysilane coupling agent on composite material containing calcium sulfite obtained from the Southern Illinois Power Co-operative. This scrubber material and the miscanthus plant are of interest due to their use in coal burning power plants to reduce toxic emission. When calcium sulfate is passed through coal fire gas emissions it absorbs mercury and sulfur. In these composites it is used as filler to reduce cost. Miscanthus is a source of both cellulose reinforcement and some natural resin. This plant has low care requirements, little mineral content, useful energy return, and positive environmental effects. Under investigation is whether a post-cure procedure or a silane coupling agent will positively impact the composite. Hot pressing alone may not be enough to fully cure the phenolic. It is hoped that the silane will increase the strength characteristics of the composite by enhancing adhesion between the calcium sulfite and phenolic resin. Possible effects on the miscanthus by the silane will also be tested. Phenolic is being utilized because of its recycling and biodegradable properties along with cost effectiveness in mass production. Composite mechanical performance was measured through 3-point bending to measure flexural strength and strain at breakage. A dynamic mechanical analyzer (DMA) was used to find thermomechanical properties. The post-cure was found to be effective, particularly on the final composite containing silane. When methyltrimethoxysilane was added to the miscanthus prior to fabrication, it was found to reduce flexural strength and density. However the addition of methyltrimethoxysilane to the calcium sulfite altered thermo-mechanical properties to a state more like pure phenolic, with added flexibility and thermal stability.

  4. Effect of hemostatic agents on properties of gelatin-alginate soft tissue adhesives.

    PubMed

    Pinkas, Oded; Zilberman, Meital

    2014-01-01

    Lacerations and traumatic wounds are considered to be among the most prevalent scenarios encountered in hospitals and emergency rooms. Reattachment of the lacerated soft tissue edges is traditionally performed using sutures. Use of tissue adhesives, i.e. substances that have the ability to firmly attach lacerated tissues back together, has raised interest as an alternative, due to several advantages. Novel tissue adhesives based on the natural polymers gelatin and alginate, and cross-linked by carbodiimide (EDC), were recently developed by our research group. In the current research, two types of hemostatic agents, tranexamic acid and kaolin, were loaded into our gelatin-alginate bioadhesive, in order to improve the adhesion abilities in the hemorrhagic environment of the wound. Their effects on the ex vivo adherence properties, physical properties, and biocompatibility were investigated. Incorporation of kaolin significantly improved the ex vivo bonding strength of the gelatin-alginate-EDC bioadhesives through a combination of three physical mechanisms and decreased the swelling ratio without affecting weight loss. In contradiction, incorporation of tranexamic acid into the bioadhesive formulation resulted in a lower ex vivo bonding strength and a higher swelling ratio and weight loss, probably due to reduced efficiency of the cross-linking reaction between the molecules of the natural polymers and the cross-linking agent EDC. The hemostatic agent-loaded bioadhesives showed good biocompatibility when tested in vitro on fibroblast cells. This research clearly shows that the incorporation of kaolin in our gelatin-alginate tissue adhesives may be a very promising novel approach for improving the bonding strength and physical properties of the tissue adhesives for use in hemorrhagic environments.

  5. Effects of Potential Therapeutic Agents on Copper Accumulations in Gill of Crassostrea virginica

    PubMed Central

    Luxama, Juan D.; Carroll, Margaret A.; Catapane, Edward J.

    2010-01-01

    Copper is an essential trace element for organisms, but when in excess, copper’s redox potential enhances oxyradical formation and increases cellular oxidative stress. Copper is a major pollutant in Jamaica Bay and other aquatic areas. Bivalves are filter feeders that accumulate heavy metals and other pollutants from their environment. Previously it was determined that seed from the bivalve Crassostrea virginica, transplanted from an oyster farm to Jamaica Bay readily accumulated copper and other pollutants into their tissues. In the present study we utilized Atomic Absorption Spectrometry to measure the uptake of copper into C. virginica gill in the presence and absence of three potential copper -blocking agents: diltiazem, lanthanum, and p-aminosalicyclic acid. Diltiazem and lanthanum are known calcium-channel blockers and p-aminosalicylic acid is an anti-infammarory agent with possible metal chelating properties. We also used the DMAB-Rhodanine histochemistry staining technique to confirm that copper was entering gill cells. Our result showed that diltiazem and p-aminosalicyclic acid reduced copper accumulations in the gill, while lanthanum did not. DMAB-Rhodanine histochemistry showed enhanced cellular copper staining in copper-treated samples and further demonstrated that diltiazem was able to reduce copper uptake. The accumulation of copper into oyster gill and its potential toxic effects could be of physiological significance to the growth and long term health of oysters and other marine animals living in a copper polluted environment. Identifying agents that block cellular copper uptake will further the understanding of metal transport mechanisms and may be beneficial in the therapeutic treatment of copper toxicity in humans. PMID:21841975

  6. Effects of diurnal variation and anesthetic agents on intraocular pressure in Syrian hamsters (Mesocricetus auratus).

    PubMed

    Rajaei, Seyed Mehdi; Mood, Maneli Ansari; Paryani, Mohammad Reza; Williams, David L

    2017-01-01

    OBJECTIVE To determine effects of diurnal variation and anesthetic agents on intraocular pressure (IOP) in Syrian hamsters (Mesocricetus auratus). ANIMALS 90 healthy adult Syrian hamsters (45 males and 45 females). PROCEDURES IOP was measured with a rebound tonometer. In phase 1, IOP was measured in all hamsters 3 times during a 24-hour period (7 am, 3 pm, and 11 pm). In phase 2, hamsters were assigned to 5 groups (18 animals [9 males and 9 females]/group). Each group received an anesthetic agent or combination of anesthetic agents (ketamine hydrochloride, xylazine hydrochloride, diazepam, ketamine-diazepam [KD], or ketamine-xylazine [KX] groups) administered via the IP route. The IOP was measured before (time 0 [baseline]) and 10, 30, 60, 90, 120, and 150 minutes after administration of drugs. RESULTS Mean ± SD IOP values were 2.58 ± 0.87 mm Hg, 4.46 ± 1.58 mm Hg, and 5.96 ± 1.23 mm Hg at 7 am, 3 pm, and 11 pm, respectively. Mean baseline IOP was 6.25 ± 0.28 mm Hg, 6.12 ± 0.23 mm Hg, 5.75 ± 0.64 mm Hg, 5.12 ± 1.40 mm Hg, and 4.50 ± 1.30 mm Hg for the ketamine, xylazine, diazepam, KD, and KX groups, respectively. A significant decrease in IOP, compared with baseline IOP, was detected in only the KX group at 30, 60, and 90 minutes after drug administration. CONCLUSIONS AND CLINICAL RELEVANCE Maximum IOP in Syrian hamsters was detected at night. The ketamine-xylazine anesthetic combination significantly decreased IOP in Syrian hamsters.

  7. Chemotherapeutic Efficacy of Indigofera aspalathoides on 20-Methylcholanthrene-Induced Fibrosarcoma in Rats

    PubMed Central

    Sivagnanam, Selva Kumar; Rao, Mudiganti Ram Krishna; Balasubramanian, Maruthaiveeran Periyasamy

    2012-01-01

    The present study was undertaken to test the chemopreventive effects of one herbal medicinal plant, Indigofera aspalathoides, on chemically induced carcinogenesis in rats. A well-known polyaromatic hydrocarbon, namely, 20-methylcholanthrene, which is a known carcinogenic substance, was used to induce fibrosarcoma in Wistar strain of male albino rats. Fibrosarcoma rats were treated with aqueous extracts of Indigofera aspalathoides. The rats were divided into four groups, each consisting of six animals. Group I served as normal control, Group II served as fibrosarcoma-induced animals, Group III were fibrosarcoma-bearing animals treated with aqueous extracts of Indigofera aspalathoides, and Group IV animals, which were normal healthy animals treated with Indigofera aspalathoides aqueous extract, served as drug control set. Group III and Group IV animals were treated with aqueous extract of Indigofera aspalathoides intraperitoneally at a dose of 250 mg/kg. b.w. for 30 days. The fibrosarcoma was proved by pathological examinations. The activity levels of nucleic acids such as total DNA and RNA and hexose, hexosamine, and sialic acid in liver and kidney of treated rats were used to monitor the chemopreventive role of the plant extract. The observed increase in the levels of DNA, RNA, hexose, hexosamine, and sialic acid in liver and kidney tissues of fibrosarcoma-bearing animals reached near normal state after the treatment with aqueous extracts of Indigofera aspalathoides, suggesting that Indigofera aspalathoides does have a chemotherapeutic role. PMID:22530134

  8. Dual-Crosslinked Methacrylated Alginate Sub-Microspheres for Intracellular Chemotherapeutic Delivery

    PubMed Central

    Scherrer, Ryan M.; Oldinski, Rachael A.

    2016-01-01

    Intracellular delivery vehicles comprised of methacrylated alginate (Alg-MA) were developed for the internalization and release of doxorubicin hydrochloride (DOX). Alg-MA was synthesized via an anhydrous reaction, and a mixture of Alg-MA and DOX was formed into sub-microspheres using a water/oil emulsion. Covalently crosslinked sub-microspheres were formed via exposure to green light, in order to investigate effects of crosslinking on drug release and cell internalization, compared to traditional techniques such as ultra violet (UV) light. Crosslinking was performed using light exposure alone, or in combination with ionic crosslinking using calcium chloride (CaCl2). Alg-MA sub-microsphere diameters were between 88 – 617 nm, and zeta-potentials were between −20 and −37 mV. Using human lung epithelial carcinoma cells (A549s) as a model, cellular internalization was confirmed using flow cytometry; different sub-microsphere formulations varied the efficiency of internalization, with UV-crosslinked sub-microspheres achieving the highest internalization percentages. While blank (non-loaded) Alg-MA sub-microspheres were non-cytotoxic to A549s, DOX-loaded sub-microspheres significantly reduced mitochondrial activity after five days of culture. Photo-crosslinked Alg-MA sub-microspheres may be a potential chemotherapeutic delivery system for cancer treatment. PMID:27378419

  9. NOVP: a novel chemotherapeutic regimen with minimal toxicity for treatment of Hodgkin's disease

    SciTech Connect

    Hagemeister, F.B.; Cabanillas, F.; Velasquez, W.S.; Meistrich, M.L.; Liang, J.C.; McLaughlin, P.; Redman, J.R.; Romaguera, J.E.; Rodriguez, M.A.; Swan, F. Jr. )

    1990-12-01

    Patients with early-staged Hodgkin's disease have had a higher relapse rate following radiotherapy alone if they have B symptoms, large mediastinal masses, hilar involvement, or stage III disease. From June 1988 to December 1989, 27 previously untreated patients with early-staged Hodgkin's disease with adverse features for disease-free survival received combined-modality therapy. Seventeen patients had stage I or II disease, 10 had stage III, 5 had B symptoms, 13 had large mediastinal masses, and 6 had peripheral masses measuring 10 cm or more in diameter. All patients initially received three cycles of a novel chemotherapeutic regimen combining Novantrone (mitoxantrone, American Cyanamid Company), vincristine, vinblastine, and prednisone (NOVP). Twenty-four patients with clinically staged I or II disease with adverse features or stage III disease did not undergo laparotomy; three patients had favorable stage I or II disease and at laparotomy had stage III disease. Radiotherapy-treatment fields depended on the extent of nodal involvement. Twenty-six patients completed all therapy as planned to complete remission (CR) and one of these has had progression; she is in second CR following additional radiotherapy. With a median follow-up of 12 months, all patients are alive. Tolerance to treatment was excellent with only grade 1 or 2 nausea, alopecia and myalgias, and brief myelosuppression. NOVP is an effective adjuvant chemotherapy regimen for inducing responses, with minimal toxicity, prior to definitive radiotherapy for patients with early-staged Hodgkin's disease.

  10. Effect of chitosan and its derivatives as antifungal and preservative agents on postharvest green asparagus.

    PubMed

    Qiu, Miao; Wu, Chu; Ren, Gerui; Liang, Xinle; Wang, Xiangyang; Huang, Jianying

    2014-07-15

    The antifungal activity and effect of high-molecular weight chitosan (H-chitosan), low-molecular weight chitosan (L-chitosan) and carboxymethyl chitosan (C-chitosan) coatings on postharvest green asparagus were evaluated. L-chitosan and H-chitosan efficiently inhibited the radial growth of Fusarium concentricum separated from postharvest green asparagus at 4 mg/ml, which appeared to be more effective in inhibiting spore germination and germ tube elongation than that of C-chitosan. Notably, spore germination was totally inhibited by L-chitosan and H-chitosan at 0.05 mg/ml. Coated asparagus did not show any apparent sign of phytotoxicity and maintained good quality over 28 days of cold storage, according to the weight loss and general quality aspects. Present results inferred that chitosan could act as an attractive preservative agent for postharvest green asparagus owing to its antifungal activity and its ability to stimulate some defense responses during storage.

  11. A call to action: training public health students to be effective agents for social change.

    PubMed

    Godwin, Hilary; Heymann, S Jody

    2015-03-01

    In the 21st century, we face enormous public health challenges that differ fundamentally from those of the last century, because these challenges involve widespread societal change and complexity. To address these challenges, public health professionals need to be able to place their work in a larger social context, understand local a